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Development and application of novel multicomponent reactions using (a)alfa-acidicisocyanidesBon, R.S.

2007

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VRIJE UNIVERSITEIT

Development and application of novel multicomponent reactions using α-acidic isocyanides

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus

prof.dr. L.M. Bouter, in het openbaar te verdedigen

ten overstaan van de promotiecommissie van de faculteit der Exacte Wetenschappen op maandag 15 januari 2007 om 15.45 uur

in de aula van de universiteit, De Boelelaan 1105

door

Robin Stefan Bon

geboren te Laren

promotor: prof.dr. M.B. Groen copromotor: dr. R.V.A. Orru

“Maturity of mind is the capacity to endure uncertainty.”

John Finley

Cover picture: http://w269.g.fiw-web.net/images/highway.jpg

Contents

Chapter 1 General Introduction

1.1 Introduction 2 1.2 Multicomponent Reactions, a Special Class of Tandem Reactions 2 1.3 Isocyanides 6 1.4 Imidazolines as Versatile Heterocycles 9 1.5 Outline of this Thesis 11 1.6 References and Notes 12

Chapter 2 Multicomponent Synthesis of 2H-2-Imidazolines: Application of α-Isocyanoacetates

2.1 Introduction 16 2.2 Multicomponent Synthesis of 2-Imidazolines from Isocyanoacetates 17 2.3 Influence of Sterically Demanding Amines and Aldehydes 21 2.4 Conclusions 22 2.5 Acknowledgements 22 2.6 Experimental Section 23 2.7 References and Notes 31

Chapter 3 Multicomponent Synthesis of 2H-2-Imidazolines: Scope Broadening

3.1 Introduction 34 3.2 MCRs with 9-Isocyanofluorene 34 3.3 MCRs with p-Nitrobenzyl Isocyanide and Allyl Isocyanide 38 3.4 Rationalisation of Difference in Reactivity Using DFT Calculations 42 3.5 Application of Ketones 44 3.6 Application of Chiral Amines and Aldehydes 46 3.7 Conclusions 48 3.8 Acknowledgements 48 3.9 Computational Details 48 3.10 Experimental Section 50 3.11 References and Notes 60

Chapter 4 Multicomponent Synthesis of NHC Complexes

4.1 Introduction 64 4.2 History of NHCs 64 4.3 Structure and Reactivity of NHCs 66 4.4 The Nature of the Metal-NHC Bond 70 4.5 Synthetic Approaches 72 4.6 Multicomponent Synthesis of NHC Precursors 76 4.7 Synthesis of NHC Complexes 79 4.8 Properties of the NHCs 87 4.9 Conclusions 89 4.10 Acknowledgements 90 4.11 Experimental Section 90 4.12 References and Notes 101

Chapter 5 Multicomponent Approaches towards Nutlin Analogues: C–2 Functionalisation of 2H-2-Imidazolines

5.1 Introduction 106 5.2 The p53 Pathway 107 5.3 Nutlins as Novel Anti-Cancer Drugs 109 5.4 Interaction of Nutlins and MDM2 111 5.5 Synthesis of Nutlins and Nutlin Analogues 111 5.6 Multicomponent Synthesis of 2H-2-Imidazolines 113 5.7 Oxidations of 2-Imidazolinium Salts 114 5.8 Liebeskind-Srogl Couplings 117 5.9 Conclusions 119 5.10 Acknowledgements 119 5.11 Experimental Section 119 5.12 References and Notes 127

Chapter 6 Multicomponent Synthesis of 3,4-Dihydro-2-pyridones

6.1 Introduction 132 6.2 Multicomponent Synthesis of 3,4-Dihydro-2-pyridones 133 6.3 Mechanistic Consideration 138 6.4 Conclusions 139 6.5 Acknowledgements 140 6.6 Computational Details 140 6.7 Experimental Section 140

6.8 References and Notes 144

Chapter 7 Retrospection and Outlook

7.1 Multicomponent Synthesis of 2H-2-Imidazolines 148 7.2 N-Heterocyclic Carbenes 149 7.3 C–2 Functionalisation of 2H-2-Imidazolines 149 7.4 Multicomponent Synthesis of 3,4-Dihydropyridin-2-ones 150 7.5 References and Notes 151

Summary 152

Samenvatting 157

Dankwoord 163

List of Abbreviations 4CC 4-component condensation Ac acetyl ACE angiotensin converting enzyme AIBN azobis(isobutyronitrile) Ar aryl Boc tert-butyloxycarbonyl br broad (spectral) Bu butyl CAN cerium(IV) ammonium nitrate cat. catalytic CDA charge decomposition analysis cod cyclooctadiene COSY correlation spectroscopy d doublet (in NMR) dd double doublet (in NMR) DCM dichloromethane DFT density functional theory DMF N,N-dimethylformamide DMSO dimethylsulfoxide DNA deoxyribonucleic acid dr diastereomeric ratio EDA energy decomposition analysis EDCI 1-(3-dimethylaminopropyl)-3-

ethylcarbodiimide hydrochloride EI electron impact (in mass spectrometry) EN exploratory power equiv. equivalent Et ethyl EWG electron withdrawing group Fc ferrocenyl HDM2 human double minute 2 HMBC heteronuclear multiple bond correlation HMQC heteronuclear multiple quantum

correlation HOMO highest occupied molecular orbital HRMS high resolution mass spectrometry IBS imidazoline binding site IMCR isocyanide multicomponent reaction IR infrared J coupling constant (in NMR) Leu leucine LUMO lowest unoccupied molecular orbital m multiplet (in NMR)

mCPBA meta-chloroperoxybenzoic acid MCR multicomponent reaction MDM2 murine double minute 2 Me methyl Mes 2,4,6-trimethylphenyl (mesityl) Mp melting point (range) MS mass spectrometry MW microwave nd not determined NHC N-heterocyclic carbene NMDA N-methyl-D-aspartate NMR nuclear magnetic resonance NOE nuclear Overhauser effect NOESY nuclear Overhauser effect spectroscopy PA proton affinity PCP para-chlorophenyl PE petroleum ether (40–60) PEA phenylethylamine PG protective group Ph phenyl Phe phenylalanine PMB para-methoxybenzyl PNP para-nitrophenyl ppm parts per million Pr propyl q quartet (in NMR) rt room temperature s singlet (in NMR) t triplet (in NMR) TFA trifluoroacetic acid THF tetrahydrofurane TLC thin layer chromatography TM transition metal TMS trimethylsilyl TosMIC tosylmethyl isocyanide Trp tryptophane Ts para-toluenesulfonyl UV ultraviolet xs excess

Chapter 1

General Introduction

This Chapter contains a brief introduction to some important topics in this thesis. First, the concept of multicomponent reactions (MCRs) as a special class of tandem reactions is explained (§ 1.2). Then, some general aspects of isocyanides are summarised (§ 1.3). A short overview of the use and synthesis of 2-imidazolines, an important class of heterocyclic scaffolds, is given in § 1.4. Finally, the scope of the thesis is outlined in § 1.5.

Chapter 1

2

1.1 Introduction

Despite recent advances in molecular biology and the progress in combinatorial synthetic methodology, the rate of introduction of new medicines has decreased markedly over the past two decades.1a Structural diversity in a focused collection of potential therapeutics is believed to increase the positive hit rate. Most medicines in use are still small synthetic organic molecules that often contain a heterocyclic ring.1 However, the range of easily accessible and suitably functionalised heterocyclic building blocks for the synthesis of structurally diverse libraries is rather limited. Therefore, the development of new, rapid and clean synthetic routes towards focused libraries of such compounds is of great importance to both medicinal and synthetic chemists.1 Undoubtedly, the most efficient strategies involve multicomponent reactions (MCRs), which have emerged as a powerful tool for the rapid introduction of molecular diversity.2 Consequently, the design and development of (new) MCRs for the generation of heterocycles receives growing interest.2

1.2 Multicomponent Reactions, a Special Class of Tandem Reactions

In traditional organic synthesis individual bonds are formed in a stepwise procedure. This often involves isolation and purification of intermediates and alteration of reaction conditions for the next synthetic step. In the ideal case, however, a target molecule is prepared from readily available starting materials in one simple, safe, environmentally friendly and resource-efficient operation that proceeds quickly and in quantitative yield (Figure 1).2a In the past decade, many research groups have aimed for the realisation of this concept of Ideal Synthesis by the development of multi-step, single operation processes for the construction of complex molecules in which several bonds are formed in a chain of events and without the necessity of isolating the intermediates. Reactions that meet these criteria, commonly referred to as tandem reactions,3 allow the economically and environmentally favourable synthesis of a wide range of organic molecules.

Figure 1. General aspects of the Ideal Synthesis


3

As suggested by Denmark, a distinction can be made between three categories of tandem reactions: i) cascade or domino reactions; ii) consecutive reactions; iii) sequential reactions.4

Scheme 1

In a tandem cascade reaction, every reaction step causes the structural change required for the next reaction step. The overall reaction proceeds without modification of reaction conditions or the addition of extra reagents. The intermediates in cascade reactions cannot be isolated. An example of a cascade reaction is depicted in Scheme 1.5

Scheme 2

Tandem consecutive reactions differ from cascade reactions in that the intermediate is an isolable entity. The intermediate contains the required functionality to undergo the second reaction step, but additional promotion in the form of energy (light or heat) is needed to overcome the activation barriers. In the consecutive reaction shown in Scheme 2, intermediate 7 can be isolated, but the application of additional heating in the same reaction vessel promotes the second Diels-Alder cyclisation.6

Scheme 3

In tandem sequential reactions, the functionalities created in the first reaction step must enable the intermediate to engage in the following reaction step. However, these types of

Chapter 1

4

reactions require the addition of an extra component for the tandem process to proceed (see for example Scheme 3).7 The intermediate may be isolable, but this is not necessary.

Figure 2. Schematic representation of a four-component reaction

A special class of tandem sequential reactions constitutes the multicomponent reaction (MCRs) (Figure 2). MCRs are defined as one-pot reactions in which three or more components react to form a single product, incorporating essentially all atoms of the starting materials.2e A MCR in which a small molecule, like water, is expelled is also referred to as a multicomponent condensation. MCRs are well appreciated because of their superior atom economy, simple procedures, the highly convergent character and the high and ever increasing number of accessible backbones.9 Different classification schemes of MCRs are possible, for example classifications according to variability, mechanisms or components involved. Although the three-component synthesis depicted in Scheme 4 gives access to 1,3-oxathiolan-2-one 17 in good yield under mild conditions and in one operation,10 this is an example of a MCR of low variability, because only the substituents on the epoxide can be varied, while the other components are fixed. This MCR is therefore of low exploratory power (EN).11

Scheme 4

Scheme 5

On the other hand, MCRs of high variability, like the tandem Petasis-Ugi reaction depicted in Scheme 5,12 are of high exploratory power, because both high complexity and


5

broad diversity are generated in this procedure. Given the numbers of commercially available starting materials, this MCR can virtually provide a library that spans a chemical space of 1000 × 500 × 1000 × 1000 × 1000 = 5 × 1014 small molecules.13

Table 1. MCRs classified by reaction mechanism

MCR type general reaction equation I A + B C O P...D II A + B C D PO... III A + B C D O P...

Based on reaction mechanisms, MCRs are divided into three subclasses, as shown in

Table 1.2a In type I MCRs, the starting materials, intermediates and products are in equilibrium with each other. The yield of the final product depends on the thermodynamics and the product is often isolated as a mixture with intermediates and starting materials. A well-known type I MCR is the Strecker reaction (Scheme 6).

Scheme 6

Type II MCRs are sequences of reversible reactions that are terminated by an irreversible reaction step, which drives the reaction to completion. This last step often involves a highly exothermic reaction like an aromatisation, a ring closure or the oxidation of the CII of isocyanides to CIV.

Scheme 7

Although they are not uncommon in biochemical pathways in living cells, type III MCRs, in which all reaction steps are irreversible, are very rare in preparative chemistry. Most successful MCRs are of type II, like the Biginelli reaction (Scheme 7). The irreversibility of the last reaction step does not exclude the formation of side products. However, very often possible side reactions are reversible as well and therefore, the irreversibly formed product P dominates. It should be noted that the classification of MCRs according to mechanism is not strict, but that transitions between the different types are fluid.

Chapter 1

6

Finally, MCRs can be classified according to the functional groups involved in the reaction. Examples are imine based MCRs, isocyanide based MCRs (IMCRs) and carbene based MCRs. Many known MCRs belong to the first type because the first step involves the condensation of an amine and an aldehyde or ketone to form an imine. One of the most famous MCRs, the Ugi four-component reaction, belongs to both imine and isocyanide based MCRs (Scheme 8).

Scheme 8

1.3 Isocyanides

Isocyanides, formerly known as isonitriles, are a class of compounds containing an extraordinary functional group. The unusual structure and reactivity of isocyanides has been discussed for more than a century.14

Figure 3. Chemical structure of isocyanides

The currently accepted representation of the isocyanide structure is depicted in Figure 3. IR studies pointed out that A contributes significantly more to the overall structure than B.15 This probably causes the remarkable stability of isocyanides as compared to carbon monoxide and carbenes.

Chart 1

Hundreds of naturally occurring isocyanides have been isolated, above all from marine species (Chart 1).16 Many of them show strong antibiotic, insecticidal, fungicidal or


7

antineoplastic effects combined with low toxicity for warm-blooded animals. Moreover, many natural products are isolated as N-formamides. As these can be regarded as either precursors or hydrolysis products of isocyanides, it is not unthinkable that many more molecules containing isocyano groups exist in Nature.

Scheme 9

The first isocyanide synthesis dates from 1859, when Lieke attempted to synthesise nitriles by the reaction of alkyl iodides with silver(I) cyanide (Scheme 9).17 When he tried to hydrolyse the resulting liquids, he was surprised to retrieve formamides instead of the expected carboxylic acids. Of course, these formamides resulted from the hydrolysis of the actual products of the alkylation of silver(I) cyanide, the isocyanides. Unfortunately, Lieke had to stop his experiments, which he performed outside, because of complaints from his neighbours about the horrible smell of the compounds. Later on, it was Gautier who discovered the isomeric relationship between isocyanides and nitriles.18 Several methods have been reported for the synthesis of isocyanides, but most lack versatility and very often, separation of the isocyanides from accompanying nitriles is difficult.2a A superior method for the exclusive generation of isocyanides, involving the dehydration of N-formamides under basic conditions, was introduced by Ugi in 1958 (Scheme 10).19 This is still the most frequently used procedure, although reagents and conditions are sometimes varied.20

Scheme 10

Although many isocyanides are solid and do not smell, most commercially available isocyanides are volatile and have a repulsive odour, ‘which is reminiscent of artichokes and phosphorous at the same time.21 People who have inhaled volatile isocyanides over a longer period report the sensory perception of the smell of hay and the increase of the intensity of dreams.2a However, apart from few exceptions, toxological studies by Bayer AG showed that most isocyanides are only slightly toxic.22

The reactivity of isocyanides is characterised by three properties: the α-acidity, the

α-addition23 and the easy formation of radicals. The radical cyclisation of phenyl isocyanides is for example used in the synthesis of the kinase inhibitor (+)-K252a 46 (Scheme 11).24

Chapter 1

8

Scheme 11

The synthetically most useful property of isocyanides is their ability to form α-adducts. Due to its doubly occupied non-bonding σ-orbital and perpendicularly positioned empty π-orbital on the same carbon, an isocyanide carbon shows nucleophilic as well as electrophilic characteristics. Most other functional groups in organic chemistry react with nucleophiles and electrophiles at different centres. Figure 4 shows that isocyanides 47 are isolobal with carbon monoxide 48 and carbenes 49 and therefore share this remarkable property with these classes of compounds.

Figure 4. Orbital pictures of an isocyanide, carbon monoxide and a (singlet) carbene

The α-acidity of isocyanides, which is further increased by additional electron withdrawing groups like esters, nitriles, phosphonates or sulfonyl groups, has been applied in the synthesis of heterocycles, α,β-unsaturated isocyanides and amino acids.25 In fact, Schöllkopf discovered that α-metalated isocyanides 50 are excellent α-amino carbanion equivalents (Scheme 12).26

Scheme 12

Isocyanide are extremely useful in the multicomponent synthesis of (depsi)peptidic structures through Ugi and Passerini reactions. Furthermore, they are widely applied in the construction of biologically relevant heterocycles such as oxazoles, oxazolines, thiazoles, thiazolines, pyrroles, imidazoles and imidazolines.27 Therefore, the isocyanides constitute a widely appreciated compound class in preparative and medicinal chemistry.


9

1.4 2-Imidazolines as Versatile Heterocycles

An important class of heterocyclic scaffolds is formed by imidazolines, also referred to as dihydroimidazoles. The most useful members of this class are the 4,5-dihydroimidazoles or 2-imidazolines (Chart 2).

Chart 2

Besides being encountered in natural products,28 2-imidazolines are also convenient building blocks for the synthesis of pharmaceutically relevant molecules, such as azapenams 60, diazapinones 61 and dioxocyclams 62 (Scheme 13).29

Scheme 13

Chart 3

Imidazoline derivatives have been studied as, amongst others, α2-adrenoceptor or estrogen receptor modulators (Chart 3).30 Their interaction with specific imidazoline binding sites results in a multiplicity of biological functions.31 Also, suitably functionalised 2-imidazolines are easily converted to 2,3-diamino acids,32 which are incorporated in a wide range of antibiotics and other biologically active compounds.33 Furthermore, chiral 2-imidazolines have attracted considerable interest as templates for asymmetric synthesis,34 as chiral ligands for asymmetric catalysis,35 and have found wide application as precursors for potent N-heterocyclic carbene (NHC) ligands in organometallic catalysis (Chart 3).36

Chapter 1

10

These possible applications render the 2-imidazoline scaffold an attractive synthetic target for several areas of research.

Typical synthetic procedures towards 2-imidazoline derivatives include ring closure of

1,2-diamines37 and base-promoted aldol reactions.38 The latter method was developed by the groups of Schöllkopf38a and Van Leusen38b simultaneously in the 1970s. Schöllkopfs procedure involves the reaction of isocyanoacetates or α-lithiated isocyanides 66 with imines 67 (Scheme 14).

Scheme 14

Van Leusen used tosylmethyl isocyanide (TosMIC) derivatives 70 as α-acidic isocyanides to synthesise imidazoles 73 via 4-tosyl-2-imidazolines 72 (Scheme 15). Based on this chemistry, a multicomponent reaction using a wide variety of TosMIC derivatives has been developed.39 Application of this MCR in combinatorial chemistry led to the discovery of pyrroloimidazoles as neurite outgrowth stimulators.40

Scheme 15

Recently, imidazoline chemistry regained attention and some catalytic diastereo- and enantioselective routes towards 2-imidazolines using chiral ferrocene-based catalysts like 76 have been reported (Scheme 16).41 This synthetic procedure only proved successful when N-tosylimines 74 were used.

Scheme 16

The only reported multicomponent synthesis of 2-imidazolines involves the TMSCl mediated 1,3-dipolar cycloaddition of oxazolones 78 to in situ generated imines, which affords C–2 substituted 2-imidazolines 79 diastereoselectively (Scheme 17).42 The diastereochemical outcome of the reaction is dictated by the oxazolone substituents.


11

Scheme 17

1.5 Outline of this Thesis

The research described in this thesis deals with: i) the exploitation of the α-acidity of isocyanides in the development of new multicomponent reactions; ii) the application of such MCRs for the synthesis of NHC complexes; and iii) the C–2 functionalisation of 2-imidazolines as a route towards libraries of potential p53-MDM2 interaction inhibitors.

In Chapter 2, the translation of Schöllkopf’s aldol type chemistry with α-isocyanoacetates

to a novel multicomponent synthesis of 2H-2-imidazolines is described. The scope of this MCR is further explored in Chapter 3 by the use of 9-isocyanofluorene and p-nitrobenzyl isocyanide as well as functionalised amines and aldehydes. Also the application of ketones instead of aldehydes and the influence of chiral inputs are addressed. Differences in reactivity of the employed isocyanides are explained using high level Density Functional Theory (DFT) calculations.

Chapter 4 contains a review on the history, structure, reactivity and synthesis of NHCs

and their metal complexes. Furthermore, the use of 2H-2-imidazolines prepared with our MCR in the synthesis of unprecedented types of NHC complexes is displayed. This procedure allows the variation of all substituents of the NHC ligands. The NHC-transition metal complexes are characterised using NMR, IR and X-ray crystal structures.

Chapter 5 starts with a comprehensive overview of the role of the p53 tumour suppressor

and its interaction with MDM2, its natural inhibitor and regulator. Then, a recently discovered class of p53-MDM2 interaction inhibitors called Nutlins is introduced and our synthetic efforts towards Nutlin analogues via the C–2 functionalisation of 2H-2-imidazolines are described.

The first part of Chapter 6 is an introduction to conformationally constrained peptides as

β-turn mimics. The next part deals with the discovery of a new MCR involving the reaction of in situ generated azadienes with α-isocyanoacetates, in which the versatile isocyano group is preserved. The products, 3-isocyano-3,4-dihydropyridones can be regarded as Freidinger type lactams suited for additional multicomponent chemistry, possibly leading to new β-turn mimics.

Chapter 1

12

In the final Chapter of this thesis, a retrospection on the different topics described in this thesis is presented. Finally, some proposals for the future elaboration of the different projects are displayed. Some parts of this thesis have been published or will be published in the near future.43

1.6 References and Notes

[1] a) Newton, R. sp2 2002 (nov.), 16–18 (see: www.sp2.uk.com). b) Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea, T. Angew. Chem. Int. Ed. Engl. 1999, 38, 3743−3748. c) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123−131. d) Schreiber, S. L. Science 2000, 287, 1964−1969.

[2] a) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. Engl. 2000, 39, 3168−3210. b) Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321−3329. c) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471−1499. d) Tempest, P. A. Curr. Opin. Drug Discovery Dev. 2005, 8, 776–788. e) Dömling, A. Chem. Rev. 2006, 106, 17–89.

[3] Some experts in the field rather refer to these processes as domino reactions (see: Tietze, L. F. Chem. Rev. 1996, 96, 115–136.) However, for the purpose of this text, it is better to consider domino reactions as a subclass of tandem reactions.

[4] Denmark, S. E.; Thorarensen, A. Chem. Rev. 2003, 96, 137–165. [5] a) Bravo, P. A.; Carrero, M. C. P.; Galan, E. R.; Blazquez, J. A. S. Heterocycles 2000, 1, 81–92. b) Franz,

A.; Eschler, P. Y.; Tharin, M.; StoeckliEvans, H.; Neier, R. Synthesis 1996, 1239–1245. [6] Kraus, G. A.; Taschner, M. J. J. Am. Chem. Soc. 1980, 102, 1974–1977. [7] Danishefsky, S.; Schuda, P. F.; Kitahara, T.; Etheredge, S. J. J. Am. Chem. Soc. 1977, 99, 6066–6075. [8] Multicomponent reactions; Zhu, J.; Bienaymé, H. (Eds.), Wiley: Weinheim, 2005. [9] Dömling, A. Curr. Opin. Chem. Biol. 2002, 6, 306–313. [10] Nishiyama, Y.; Katahira, C.; Sonoda, N. Tetrahedron Lett. 2004, 45, 8539–8540. [11] The concept of the exploratory power of a reaction has been introduced in: Bienaymé, H.; Hulme, C.;

Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321–3329. [12] Portlock, D. E.; Naskar, D.; West, L.; Ostaszewski, R.; Chen, J. J. Tetrahedron Lett. 2003, 44, 5121–5124. [13] The corresponding starting materials of these reactions are commercially available, mostly in numbers

exceeding 1000 (RCO2H, RNH2, RCHO, RCOR). However, less than 1000 boronic acids are available at the moment.

[14] Ugi, I. Isonitrile Chemistry, Academic Press, London 1971, ISBN: 0-12-706150-9. [15] Sidgwick, N. V. Chem. Rev. 1931, 9, 77–88. [16] For reviews, see: a) Scheuer, P. J. Acc. Chem. Res. 1992, 25, 433–439. b) Edenborough, M. S.; Herbert, R. B.

Nat. Prod. Rep. 1988, 5, 229–245. [17] Lieke, W. Justus Liebigs Ann. Chem. 1859, 112, 316. [18] Gautier, A. Justus Liebigs Ann. Chem. 1869, 146, 119 [19] a) Ugi, I.; Meyr, R. Angew. Chem. 1958, 70, 702–703. b) Ugi, I.; Meyr, R. Chem. Ber. 1960, 93, 239–248. [20] Common dehydration reagent/base couples are (tri)phosgene/NMM, diphosgene/DIPEA, POCl3/Et3N and

TsCl/pyridine. [21] Gautier, A. Ann. Chim. (Paris) 1869, 17, 218. [22] Values of LD50 = 1–5 g per kg of body weight (mouse) upon subcutaneous and/or oral administration are no

exception. However, 1,4-diisocyanobutane is extremely toxic according to test carried out by Bayer AG (LD50 < 10 mg kg−1).

[23] The α-acidity refers to the acidity of the CH in the α-position of the isocyano group. The α-addition refers to additions to the isocyanide carbon.

[24] Kobayashi, Y.; Fukuyama, T. J. Heterocycl. Chem. 1998, 35, 1043–1055.


13

[25] Hoppe, D. Angew. Chem. Int. Ed. Engl. 1974, 13, 789–804. [26] Schöllkopf, U. Angew. Chem. 1977, 89, 351–360. [27] For a comprehensive review on heterocycle synthesis with isocyanides see: Marcaccini, S.; Torroba, T. Org.

Prep. Proced. Int. 1993, 25, 141–208. [28] For example see: Hassner, A.; Fischer, B. Heterocycles 1993, 35, 1441−1465. [29] a) Betschart, C.; Hegedus, L. S. J. Am. Chem. Soc. 1992, 114, 5010−5017. b) Hsiao, Y.; Hegedus, L. S. J.

Org. Chem. 1997, 62, 3586−3591. [30] a) Schäfer, U.; Burgdorf, C.; Engelhardt, A.; Kurz, T.; Richardt, G. J. Pharmacol. Exp. Ther. 2002, 303,

1163−1170. b) Rondu, F.; le Bihan, G.; Wang, X.; Lamouri, A.; Touboul, E.; Dive, G.; Bellahsene, T.; Pfeiffer, B.; Renard, P.; Guardiola-Lemaitre, B.; Manechez, D.; Penicaud, L.; Ktorza, A.; Godfroid, J.-J. J. Med. Chem. 1997, 40, 3793−3803. c) Gust. R.; Keilitz, R.; Schmidt, K. J. Med. Chem. 2001, 44, 1963−1970. d) Gust, R.; Keilitz, R.; Schmidt, K.; Von Rauch, M. J. Med Chem. 2002, 45, 3356−3365.

[31] Gentili,F.; Bousquet, P.; Brasili, L.; Dontenwill, M.; Feldman, J.; Ghelfi, F.; Gianella, M.; Piergentili, A.; Quaglia, W.; Pigini, M. J. Med. Chem. 2003, 46, 2169−2176.

[32] Zhou, X.-T.; Lin, Y.-R.; Dai, L.-X. Tetrahedron: Asymmetry 1999, 10, 855–862. [33] a) Dunn, P. J.; Haner, R.; Rapoport, H. J. Org. Chem. 1990, 55, 5017−5025 and references cited therein. b)

Han, H.; Yoon, J.; Janda, K. D. J. Org. Chem. 1998, 63, 2045−2048. [34] a) Jones, R. C. F.; Howard, K. J.; Snaith, J. S. Tetrahedron Lett. 1996, 37, 1707−1710. b) Jones, R. C. F.;

Howard, K. J.; Snaith, J. S. Tetrahedron Lett. 1996, 37, 1711−1714. c) Dalko, P. I.; Langlois, Y. Chem. Commun. 1998, 331−332.

[35] Menges, F.; Neuburger, M.; Pfaltz, A. Org. Lett. 2002, 4, 4713−4716. [36] Herrmann, W. A. Angew. Chem. Int. Ed. Engl. 2002, 41, 1290−1309 and references cited therein. [37] a) Riebsomer, J. L. J. Am. Chem. Soc. 1948, 70, 1629−1631. b) Jones, R.C.F.; Howard, K.J.; Snaith, J.S.

Tetrahedron Lett. 1996, 37, 1707−1710. [38] a) Meyer, R.; Schöllkopf, U.; Böhme, P. Liebigs Ann. Chem. 1977, 1183−1193. b) van Leusen, A. M.;

Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977, 42, 1153−1159. [39] a) Sisko, J.; Kassick, A.J.; Mellinger, M.; Filan, J.J.; Allen, A.; Olsen, M.A. J. Org. Chem. 2000, 65,

1516−1524. b) Sisko, J.; Mellinger, M. Pure Appl. Chem. 2002, 74, 1349–1357. [40] Beck, B.; Leppert, C. A.; Mueller, B. K.; Dömling, A. QSAR Comb. Sci. 2006, 25, 527–535. [41] a) Hayashi, T.; Kishi, E.; Soloshonok, V.A.; Uozumi, Y. Tetrahedron Lett. 1996, 37, 4969−4972. b) Lin, Y.-R.;

Zhou, X.-T.; Dai, L.-X.; Sun, J. J. Org. Chem. 1997, 62, 1799−1803. c) Zhou, X.-T.; Lin, Y.-R.; Dai, L.-X.; Sun, J.; Xia, L.-J.; Tang, M.-H. J. Org. Chem. 1999, 64, 1331−1334.

[42] a) Peddibhotla, S.; Jayakumar, S.; Tepe, J.J. Org. Lett. 2002, 4, 3533−3535. b) Sharma, V.; Tepe, J. J. Org. Lett. 2005, 7, 5091–5094.

[43] a) Bon, R. S.; Hong, C.; Bouma, M. J.; Schmitz, R. F.; de Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Orru, R. V. A. ‘Novel Multi-component Reaction for the Combinatorial Synthesis of 2-Imidazolines’ Org. Lett. 2003, 5, 3759–3762. b) Bon, R. S.; van Vliet, B.; Sprenkels, N. E.; Schmitz, R. F.; de Kanter, F. J. J.; Stevens, C. V.; Swart, M.; Bickelhaupt, F. M.; Groen, M. B.; Orru, R. V. A. ‘Multi-component Synthesis of 2-Imidazolines’ J. Org. Chem. 2005, 70, 3542–3553. c) Paravidino, M; Bon, R. S.; Scheffelaar, R.; Vugts, D. J.; Znabet, A.; Schmitz, R. F.; de Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Groen, M. B.; Orru, R. V. A. ‘Multicomponent Synthesis of 3,4-Dihydropyridones’ Org. Lett. 2006, 8, 5369–5372. d) Bon, R. S.; Schmitz, R. F.; de Kanter, F. J. J.; Ehlers, A. W.; Lutz, M.; Spek, A. L.; Jahnke, M. C.; Hahn, F. E.; Groen, M. B.; Orru, R. V. A. ‘Multicomponent Synthesis of N-Heterocyclic Carbene Complexes’ submitted. e) Bon, R. S.; Sprenkels, N. E.; Koningstein, M. M.; Schmitz, R. F.; de Kanter, Dömling, A.; Groen, M. B.; Orru, R. V. A. ‘C–2 Functionalization of 2-Imidazolines: MCR Approaches toward Nutlin Analogues’ in preparation.

Chapter 2

Multicomponent Synthesis of 2H-2-Imidazolines

Application of α-Isocyanoacetates

Robin S. Bon,a Chongen Hong,a Marinus J. Bouma,a Tanja Eichelsheim,a Rob F. Schmitz,a Frans J.J. de Kanter,a Martin Lutz,b

Anthony L. Spek,b Romano V.A. Orrua

aDepartment of Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands

bBijvoet Center for Biomolecular Research, Crystal and Structural Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands

Parts of this Chapter have been published in: Org. Lett. 2003, 5, 3759–3762

J. Org. Chem. 2005, 70, 3542–3553

Abstract: A multicomponent reaction between amines, aldehydes and methyl 2-isocyano-2-phenylacetate gives easy access to a diverse range of highly substituted 2H-2-imidazolines. The method is compatible with a wide range of amines and aldehydes, although steric congestion around the imine carbon slows down or even prevents the reaction. In general, the trans-diastereomers are formed predominantly, which was proven using X-ray crystal structure determination and NMR analysis.

Chapter 2

16

2.1 Introduction

Except from the highly diastereoselective synthesis of C-2 substituted 2-imidazolines from oxazolones,1 known 2-imidazoline syntheses were performed in a stepwise fashion and were not set-up as MCR. They are therefore not suited for the combinatorial synthesis of small focused libraries of 2-imidazolines. Our main objective was the translation of the aldol synthesis of 2H-2-imidazolines to an elegant and flexible MCR and to determine its scope with respect to the input components. We envisioned a MCR towards imidazolines of type 6 to proceed through in situ formation of imines 3 from amines 1 and aldehydes 2, followed by attack of (the α-carbanion of) an isocyanide bearing an acidic α-proton 4 and subsequent ring closure (Scheme 1). Traces of amine present in the reaction mixture may act as basic catalyst to promote α-addition generating the tentative intermediate 5.2

Scheme 1

As additional electron withdrawing group (EWG) in isocyanide 4, we considered a wide range of functional groups, including ketones, esters, amides, nitriles and sulfonyl groups. Although the sulfonyl group is a suitable EWG, cycloaddition of TosMICs 4e (R8 = tolyl) to imines 3 is mostly followed by elimination of sulfinic acid, leading to imidazoles.3 The synthesis of oxazolines via cycloaddition of several α-isocyanoacetonitriles 4d (R3 = H, Me, iPr) to aldehydes or ketones has been reported.4 Synthesis of the highly unstable α-isocyanoacetonitriles is not trivial though.5 Only few α-isocyanoketones 4a are known, and they easily isomerise to the corresponding oxazoles.6 Therefore, our focus was on the α-isocyanoacetates 4b and α-isocyanoacetamides 4c, which can be easily prepared from the corresponding α-amino acids.

Chart 1

The pKa(αCH) of an amide is 2–4 units higher than that of an ester. Consequently, the α-isocyanoacetamides 4c will be less easily deprotonated than the α-isocyanoacetates 4b.7 Furthermore, the Lewis basicity of the amide oxygen of 4c, as compared to the ester oxygen of 4b, is significantly higher. These characteristics of α-isocyanoacetamides are illustrated

Multicomponent Synthesis of 2H-2-Imidazolines: Application of α-Isocyanoacetates

17

by the work of Zhu et al., who applied α-isocyanoacetamides 4c for the development of a variety of new MCRs.8 In these reactions, the key step is the addition of the isocyano group of 4c to in situ generated imines 3 to produce nitrilium intermediate 7, succeeded by tautomerisation and cyclisation to oxazoles 8 (Scheme 2).

Scheme 2

The oxazoles can undergo various follow-up reactions, like (intra- and intermolecular) Diels-Alder reactions or hydrolysis to a bisamide. Using these diverse follow-up reaction conditions and different work-up procedures, a plethora of complex polyheterocycles8 and macrocycles9 is accessible (examples can be found in Chart 2).

Chart 2

Considering the previous, α-isocyanoacetates 4b were believed to be the most promising reagents in the envisioned multicomponent synthesis of 2H-2-imidazolines.

2.2 Multicomponent Synthesis of 2-Imidazolines from α-Isocyanoacetates

Having in mind Schöllkopf’s imidazoline synthesis,2 it seemed reasonable to explore the reactivity of methyl isocyanoacetate 6 in MCRs. However, the initial results for the MCR combining 15 with benzylamine 13 and benzaldehyde 14 were disappointing (Table 1). Even after prolonged stirring in MeOH, only traces of imidazoline 16 were formed (entry 1). Also, in our hands, duration of reactions between 15 and the preformed imine of 13 and 14 proved significantly longer than those reported earlier.10 However, when the reaction was performed at a larger scale (entry 2) a reasonable amount of 16 could be isolated. On the other hand, stirring the same components in DCM gave no detectable imidazoline 16.

Chapter 2

18

Table 1. Multicomponent Synthesis of 2H-2-Imidazolines from 6

entry conditions scale (mmol) yielda (%)

1 MeOH, rt, 3d 1 <5b

2 MeOH, rt, 18h 5 34b

3 DCM, rt, 3d 1 0 a Isolated yields are reported. b Only the trans-diastereomer (1H NMR)

of 16 was found.

Interesting in this respect is that isocyanoacetate 15 can be easily applied in Ugi four

component condensations (Ugi-4CC).11 A reaction between 15, isopropylamine 17, isobutyraldehyde 18 and propionic acid 19 provides the bisamide 20 in 81% yield (Scheme 3).

Scheme 3

Methyl 2-isocyano-2-phenylacetate 23 has a more acidic α-H compared to 15 and should serve as a more appropriate isocyanide component in the MCR of Scheme 1. Racemic 23 was synthesised from D-phenylglycine methyl ester 21 via the N-formamide 22 in 88% yield (Scheme 4).12 Isocyanoacetate 23 turned out to be somewhat unstable towards silica column chromatography and has an unpleasant odour. For high yields, vacuum distillation is the best purification method. Other reagents for the dehydration of N-formamide 22 were tested, like POCl3/Et3N, Burgess' reagent,13 and TsCl/pyridine. Unfortunately, no optically active isocyanide could be obtained.

Scheme 4a

a Reagents and conditions: (a) acetic formic anhydride, DCM, 0 ºC to rt, 1 h; (b) NMM, triphosgene, DCM, −30

ºC to −5 ºC, 3 h.


19

The MCR between 23, 17 and 18 afforded the desired imidazolines 24 in reasonable yields depending on the solvent used (Table 2). In MeOH, DCM and toluene comparable yields were obtained (entries 1–3), whereas in THF, almost no formation of 24 was observed (entry 4). It is important to note that the use of carboxylic acid 19 together with 17, 18 and 23, in a procedure similar to that described above for 6 (Scheme 3) only gave 24. The expected Ugi-4CC product was not formed. Apparently, the carboxylic acid does not participate in this MCR.

Table 2. Multicomponent Synthesis of 2H-2-Imidazolines from 23

entry solvent yielda (%) ratio 24a : 24bb,c 1 MeOH 67 75:25 2 DCM 74 75:25 3 toluene 62 75:25 4 THF 10 75:25

a Isolated yields are reported. b Diastereomeric ratios were calculated from 1H NMR spectra. c Relative stereochemistry of 24a was determined using X-ray diffraction.

Formation of the trans-diastereomer 24a is favoured over formation of the cis-diastereomer 24b. The ratio is independent of the solvent used (Table 2). X-ray data of 24a unambiguously proved the trans relationship between the methyl ester at C–4 and isopropyl substituent at C–5 (Figure 1).

Figure 1. Displacement ellipsoid plot of 24a. Drawn at the 50% probability level. Hydrogen atoms are omitted for clarity.

Chapter 2

20

The scope of this MCR was further elaborated. Following the optimal conditions for the formation of 24 (DCM, Na2SO4, 18 h, rt), one-pot combination of 23 with functionalised aliphatic, aromatic, or benzylic amines and aliphatic, (hetero)aromatic, or α,β-unsaturated aldehydes provided a range of imidazolines (Table 1).

Table 3. Series of 2H-2-imidazolines synthesised from 23

entry amine aldehyde product a yield (dr)b

1 NH2

Ph Ph

25 O

18 N

N

Ph

PhPh

MeO2C26

13% (66:34)

2 PMBNH227

O18 N

N

Ph

PMB

MeO2C28

73% (76:24)

3 PhNH2

29 O

18 N

N

Ph

Ph

MeO2C30

53% (70:30)

4 NH2

17 O

OMe

31 N

N

PhMeO2C

MeO

32

77% (70:30)

5 PMBNH227 O

OMe

31 N

N

Ph

PMB

MeO2C

MeO

33

90% (55:45)

6 NH2

17 O

O

34 N

N

PhMeO2C

O

35

81% (76:24)

7 PMBNH227 O

O

34 N

N

Ph

PMB

MeO2CO

36

91% (70:30)

8 NH2

17 O

N

37 N

N

PhMeO2C

N

38

71% (84:16)

9 OH2N

39 O

CO2Et

40 N

N

PhMeO2C

EtO2C O

41

47% (67:33)

a Only the major diastereomer is depicted. b Isolated yields are reported. Ratios (dr) refer to trans:cis.


21

Reactions went smoothly and the products were obtained in fair to good yields (47–91%), except from the reaction with sterically demanding benzhydrylamine 25 (entry 1). In this case, considerable amounts of imine are isolated. The assumption that imidazoline formation with benzhydrylamine proceeds relatively slow is supported by the observation that combination of 25, 18, 19 and 23 only gave (within 18 h) the corresponding Ugi-4CC product in 60% yield. In analogy with 24a, whose relative configuration was confirmed by X-ray crystal structure determination (vide supra), 1H NMR data were used to assign the relative configuration at C-4 and C-5 for the new 2-imidazolines. Analysis of all 1H NMR spectra revealed for H-5 a characteristic Δδ(trans−cis) = 0.6 ± 0.05 ppm. The upfield shift of H-5 in the spectra of the trans-diastereomers can be explained by a shielding effect of the Ph-group at C-4. This is confirmed by NOE-measurements. Without exception, the trans-products were formed predominantly. Interestingly, Spartan semi-empirical PM3 calculations show that, in general, the cis-diastereomers are energetically favoured over the trans-isomers. However, the calculations suggest that formation of the trans-diastereomers proceeds via favoured intermediates 5 and is easier then formation of the cis-diastereomers.

2.3 Influence of Sterically Demanding Amines and Aldehydes

Steric factors were believed to cause the disappointing yields for MCRs with benzhydrylamine and isobutyraldehyde as the amine and aldehyde components, respectively. In order to investigate if these factors indeed determine the limitations of the MCR, a series of sterically more and less demanding amines and aldehydes was tested in combination with isocyanoacetate 23 (Table 4).

Table 4. The influence of sterically demanding amine and aldehyde substituentsa,b

R1 = Hc R1 = iPr R1 = tBu R1 = Mes R1 = CHPh2

R2 = Hd 42a, <5%e,f 42b, 70% 42c, 86% 42d, 65% 42e, 82% R2 = iPr 42f, 76% (68:32) 24, 74% (75:25) 42g, 21% (trans) 42h, <5%e 26, 13% (66:34) R2 = tBu 42i, 56%g (78:22) 42j, <5%e 42k, <5%h 42l, <5%e 42m, <5%e R2 = Mes 42n, 67% (trans) 42o, <5%e 42p, 15% (trans) 42q, <5%e 42r, 17% (74:26)

a Isolated yields and diastereomeric ratios are reported, unless stated otherwise. b Structures containing asymmetric carbons represent racemic compounds. c A solution of 2N NH3 in MeOH was used. d Paraformaldehyde was used. e In the 1H NMR spectrum of the crude product, no 2-imidazoline could be observed. f The corresponding 2-oxazoline was isolated in quantitative yield. g Yield after stirring for 3 days. After a reaction time of 18 hours, only 20% of 42i could be isolated. h The corresponding 2-oxazoline was isolated in 10% yield.

Chapter 2

22

The application of bulky amines like tert-butylamine, 2,4,6-trimethylaniline or benzhydrylamine results in diminished yields of the 2-imidazolines (42gkp, 42hlq, 26 and 42mr, respectively), unless a very small aldehyde like formaldehyde is used (42c–42e). On the other hand, sterically demanding aldehydes like pivaldehyde and mesitaldehyde react even more sluggishly. Not only do they give no detectable formation of 2-imidazoline in combination with the moderately bulky iso-propylamine (42j and 42o), a tert-butyl group on the aldehyde even slows down the reaction significantly when ammonia is used as the amine component (42i), although the isolated yield of 42i was still reasonable after prolonged stirring at room temperature. Application of mesitaldehyde together with ammonia proved to be satisfying (42n). It is unlikely that low yields are due to sluggish imine formation, because in general, considerable amounts of imine could be recovered after the reaction.

The presence of one or two moderately bulky groups on the in situ formed imine does not hinder the aldol-type addition (42b, 42f, and 24), but, surprisingly, combination of ammonia, paraformaldehyde and 23 furnished only the 2-oxazoline, resulting from a reaction between the in situ generated formaldehyde and isocyanoacetate 23.14 In conclusion, the results presented in Table 4 indicate that steric congestion around the imine carbon indeed influences the aldol-type addition step of the 2-imidazoline formation (towards the proposed intermediate 5 in Scheme 1). Furthermore, they suggest that only one sterically demanding group on the in situ formed imine is allowed.

2.4 Conclusions

In summary, the step-wise aldol synthesis of 2H-2-imidazolines was successfully translated to a flexible MCR suited for combinatorial application. Methyl 2-isocyano-2-phenylacetate 23 proved to be an excellent isocyanide component. The results indicate that the MCR is compatible with a wide range of amine and aldehyde components, although steric bulk on the imine intermediate causes a significant drop of the reaction rate. Evidently, the acidity of the α-proton of the employed isocyanide is crucial to the ease with which the reaction can be performed, as the application of methyl isocyanoacetate 15 was less successful. The trans-imidazolines are always favoured over their cis-isomers.

2.5 Acknowledgements

Dr. Marek Smoluch (Vrije Universiteit Amsterdam) and Dr. Maarten Posthumus (Agricultural University Wageningen) are gratefully acknowledged for conducting (HR)MS measurements. This work was partially supported (M.L., A.L.S.) by the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (CW-NWO).


23

2.6 Experimental Section

General Information: All reactions were carried out under an inert atmosphere of dry nitrogen. Standard syringe techniques were applied for transfer of air sensitive reagents and dry solvents. Melting points were measured using a Stuart Scientific SMP3 melting point apparatus and are uncorrected. Infrared (IR) spectra were obtained from CHCl3 films on NaCl tablets (unless noted otherwise), using a Matteson Instuments 6030 Galaxy Series FT-IR spectrophotometer and wavelengths (ν) are reported in cm−1. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 (400.13 MHz and 100.61 MHz respectively) or a Bruker Avance 250 (250.13 MHz and 62.90 MHz respectively) with chemical shifts (δ) reported in ppm downfield from tetramethylsilane. MS and HRMS spectra data were recorded on a Finnigan Mat 900 spectrometer or in the Laboratory of Organic Chemistry of the Wageningen University (NL) on a Finnigan MAT95 spectrometer. Chromatographic purification refers to flash chromatography using the indicated solvent (mixture) and Baker 7024-02 silica gel (40μ, 60 Å). Thin Layer Chromatography was performed using silica plates from Merck (Kieselgel 60 F254 on aluminium with fluorescence indicator. Compounds on TLC were visualised by UV-detection. THF and Et2O were dried and distilled from sodium benzophenone ketyl prior to use. DCM was dried and distilled from CaH2 prior to use. Petroleum ether (PE 40–65) was distilled prior to use. Triethylamine and isopropylamine were dried and distilled from KOH pellets. Furfural, isobutyraldehyde and benzaldehyde were distilled and stored over MS 4Å under a dry nitrogen atmosphere. Propionic acid was purified by drying with Na2SO4 and subsequent fractional distillation. Phosphoryl chloride was distilled from P2O5 and stored under a dry nitrogen atmosphere. Acetic formic anhydride was prepared by stirring 1 equiv. of acetic anhydride and 1.2 equiv. of formic acid for 2 h at 55°C used as such. Other commercially available reagents were used as purchased.

(trans)-Methyl 1-benzyl-5-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 16. Na2SO4 (2 g) and benzaldehyde 14 (0.51 mL, 5.0 mmol) were added to a stirring solution of benzylamine 13 (0.55 mL, 5.0 mmol) in 15 mL MeOH at rt,. After 2 h, methyl isocyanoacetate 15 (495 mg, 5.0 mmol) was added and stirring was continued for 18 h. The reaction mixture was filtered and

concentrated in vacuo. Purification by column chromatography (PE:EtOAc:Et3N = 2:1:0.01, gradient) afforded 16 as a single diastereomer (498 mg, 34%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.30–7.14 (m, 8H), 7.08–6.97 (m, 3H), 4.60 (d, J = 9.4 Hz, 1H), 4.50 (dd, J = 9.4, 1.8 Hz, 1H), 4.29 (d, J = 14.9 Hz, 1H), 3.84 (d, J = 14.9 Hz, 1H), 3.63 (s, 3H); 13C NMR (101 MHz): δ (ppm) 172.5 (C), 157.2 (CH), 140.0 (C), 136.0 (C), 129.4 (2×CH), 129.2 (2×CH), 128.7, 128.4 (2×CH), 128.3, 127.7 (2×CH), 78.4 (CH), 66.0 (CH), 52.8 (CH3), 43.4 (CH2); IR (neat): 1740 (s), 1597 (s), 1221 (s).

Bisamide 20. Na2SO4 (1 g) and isobutyraldehyde 18 (144 mg, 2.0 mmol) were added to a stirred solution of isopropylamine 17 (118 mg, 2.0 mmol) in 3 mL DCM at rt,. After stirring for 2 h, propionic acid 19 (148 mg, 2.0 mmol) was added. Stirring was continued for 0.5 h and methyl isocyanoacetate 15 (120 mg, 1.3 mmol) was added to

the reaction mixture. After 18 h, the reaction mixture was poured into 4 mL water. The layers were separated and the aqueous layer extracted with 3 mL DCM. The combined organic layers were washed with water (3 mL), brine (3 mL), dried with Na2SO4 and concentrated in vacuo. Purification by column chromatography (PE:EtOAc = 2:1) afforded the bisamide 20 (384 mg, 81%) as a colourless oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.74 (br s, 1H), 4.09 (m, 1H), 4.04 (dd, J = 17.8, 6.4 Hz, 1H), 3.87 (dd, J = 17.8, 5.5 Hz, 1H), 3.70 (s, 3H), 3.20 (m, 1H), 3.02 (m, 1H), 2.44 (m, 2H), 1.23 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.5 Hz, 3H), 1.17 (t, J = 7.5 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 175.4 (C), 173.9 (C), 170.2 (C), 68.0 (CH), 52.3 (CH3), 50.0 (CH), 40.8 (CH2), 28.3 (CH2), 26.8 (CH), 21.1 (CH3), 20.7 (CH3), 20.3 (CH3), 19.8 (CH3), 9.7 (CH3); IR (neat): 3294 (br) 2972 (s), 1755 (s), 1672 (s), 1626 (s), 1537 (s), 1441 (s).

(R)-Methyl 2-formamido-2-phenylacetate 22. Acetic formic anhydride (25 mL) was added dropwise to a stirred solution of D-phenylglycine methyl ester 21 (11.33 g, 68.7 mmol) in 150

N

NPh

MeO2C

Ph

Ph

NH

CO2MeO

NH

NO

OMeO2C

Chapter 2

24

mL dry DCM at 0°C. Stirring was continued for 1 h at rt. Evaporation of the solvent and acids at reduced pressure yielded the N-formamide 22 (13.1 g, 99%) as a yellow oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 8.27 (br s, 1H), 7.43–7.32 (m, 5H), 6.67 (br s, 1H), 5.70 (d, J = 12.4 Hz, 1H), 3.76 (s, 3H). [α]D

23 –237° (c 1.00, DCM). Methyl 2-isocyano-2-phenylacetate 23. NMM (1.57 mL, 14.3 mmol) was added to a stirred solution of 22 (791 mg, 4.09 mmol) in 10 mL dry DCM at −30°C. After this, triphosgene (504 mg,

1.7 mmol) THF was added and the reaction mixture was stirred for 30 minutes and then allowed to warm up to −5 ºC. After stirring for another 3 h, the reaction mixture was quenched in ice cold water (10 mL). Layers were separated and the aqueous layer extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (40 mL), dried with Na2SO4 and concentrated in vacuo. Kugelrohr distillation afforded 23 (638 mg, 89%) as a yellow/orange oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.43–7.29 (m, 5H), 5.21 (s, 1H), 3.70 (s, 3H); 13C NMR (101 MHz): δ (ppm) 166.5 (C), 161.9 (C), 132.2 (C), 130.0 (2×CH), 129.6 (2×CH), 127.1 (CH), 60.6 (CH, broad signal), 54.1 (CH3); IR (neat): 2151 (s), 1757 (s). General Procedure I for the Synthesis of 2-Imidazolines: Reactions were carried out at a concentration of 1 M of amine, 1 M of aldehyde and 0.5 M of isocyanide in dry DCM, unless noted otherwise. Na2SO4 and the aldehyde were added, at rt, to a stirred solution of the amine. After the mixture was stirred for 2 h, the isocyanide was added and the reaction mixture was stirred at rt for an additional 18 h. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (PE:EtOAc:Et3N = 2:1:0.01, gradient, unless stated otherwise).

Methyl 1,5-diisopropyl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 24. According to General Procedure I, reaction between isopropylamine 17 (236 mg, 4.0 mmol), isobutyraldehyde 18 (288 mg, 4.0 mmol) and isocyanoacetate 23 (330 mg, 1.84 mmol), followed by column chromatography, afforded 24 (389 mg, 74%) as a 75:25 mixture of diastereomers as a yellow

solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.66 (d, J = 7.2 Hz, 2H) 7.45–7.17 (m, 6H + 4H), 4.46 (d, J = 1.6 Hz, 1H), 3.77 (d, J = 2.2 Hz, 1H), 3.70 (s, 3H), 3.67 (s, 3H), 3.49 (m, 1H), 3.31 (m, 1H), 2.54 (m, 1H), 1.61 (m, 1H), 1.40 (d, J = 6.8 Hz, 3H), 1.36 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.09 (d, J = 7.2 Hz, 3H), 0.96 (d, J = 7.3 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.4 Hz, 3H), 0.41 (d, J = 6.7 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 174.8 (C), 172.9 (C), 153.2 (CH), 153.1 (CH), 145.2 (C), 137.6 (C), 127.9 (2×CH), 127.8 (2×CH), 127.6 (2×CH), 127.3 (CH), 127.2 (CH), 126.3 (2×CH), 83.6 (C), 80.9 (C), 74.2 (CH), 67.7 (CH), 52.7 (CH3), 52.4 (CH3), 48.7 (CH), 48.2 (CH), 29.6 (CH), 28.9 (CH), 22.5 (CH3), 22.4 (CH3), 22.3 (CH3), 21.9 (CH3), 21.5 (CH3), 21.4 (CH3), 16.1 (CH3), 15.4 (CH3); IR (neat): 2967 (s), 1722 (s), 1589 (s), 1576 (s), 1464 (s), 1447 (s), 1215 (s). Slow crystallisation from Et2O afforded the pure diastereomer 24a as white crystals. Mp 124.9–125.2 oC; 1H NMR (250 MHz, CDCl3): δ (ppm) 7.47–7.25 (m, 5H), 7.18 (s, 1H), 4.46 (d, J = 1.6 Hz, 1H), 3.67 (s, 3H), 3.49 (m, 1H), 1.61 (m, 1H), 1.40 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 0.96 (d, J = 7.3 Hz, 3H), ), 0.41 (d, J = 6.7 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 175.2 (C), 153.6 (CH), 138.0 (C), 128.2 (2×CH), 128.0 (2×CH), 127.7 (CH), 84.0 (C), 68.1 (CH), 53.2 (CH3), 48.6 (CH), 29.3 (CH), 22.9 (CH3), 22.8 (CH3), 21.9 (CH3), 15.8 (CH3); IR (KBr): 2969 (s), 1713 (s), 1587 (s), 1574 (s), 1129 (s), 1215 (s), 1198 (s); MS (EI, 70 eV): m/z (%) = 288 (0.5) [M]+, 229 (100) [M−CO2Me]+, 187 (45), 145 (31); HRMS (EI, 70 eV) calculated for C17H24N2O2 (M+) 288.1838, found 288.1835.

Crystallographic Data for 24a. C17H24N2O2, fw = 288.38, Temp = 150(2) K; orthorhombic, Pbca (no. 61), a = 16.8620(2), b = 11.0458(1), c = 16.9723(2) Å, V = 3161.16(6) Å3, Dx = 1.212 g/cm3, 39712 measured refl., 3612 unique reflections (Nonius KappaCCD diffractometer, λ = 0.71073 Å). R1/wR2 [I >2 σ(I)] = 0.0386/0.0986; R1/wR2 [all refl.] = 0.0537/0.1070; GoF = 1.085. Residual electron density between −0.19 and 0.25 e/Å3.

N

N

PhMeO2C

N

NO

O

N12

N3

45

6

719

8O9

10

O20

11

12

1314

15

16

1718

21


25

Table 5. Bond distances of the non-hydrogen atoms (Å) of 24a (standard deviations)

O(9)-C(8) 1.3280(13) C(4)-C(5) 1.5647(15) C(12)-C(13) 1.3928(17) O(9)-C(10) 1.4485(15) C(4)-C(8) 1.5503(15) C(13)-C(14) 1.3887(18) O(20)-C(8) 1.2033(14) C(4)-C(11) 1.5231(15) C(14)-C(15) 1.3789(17) N(1)-C(2) 1.3583(16) C(5)-C(17) 1.5383(15) C(15)-C(16) 1.3930(17) N(1)-C(5) 1.4762(13) C(6)-C(7) 1.5217(18) C(17)-C(18) 1.5269(17) N(1)-C(6) 1.4743(15) C(6)-C(19) 1.5189(18) C(17)-C(21) 1.5279(16) N(3)-C(2) 1.2868(15) C(11)-C(12) 1.3976(16) N(3)-C(4) 1.4956(14) C(11)-C(16) 1.3923(16)

Table 6. Bond angles of the non-hydrogen atoms (º) of 24a (standard deviations) C(8)-O(9)-C(10) 116.25(9) C(8)-C(4)-C(11) 106.69(8) C(4)-C(11)-C(16) 120.92(10) C(2)-N(1)-C(5) 107.15(9) N(1)-C(5)-C(4) 99.86(8) C(12)-C(11)-C(16) 118.97(10) C(2)-N(1)-C(6) 124.97(9) N(1)-C(5)-C(17) 110.60(9) C(11)-C(12)-C(13) 120.30(10) C(5)-N(1)-C(6) 123.69(9) C(4)-C(5)-C(17) 117.36(9) C(12)-C(13)-C(14) 120.13(11) C(2)-N(3)-C(4) 104.12(9) N(1)-C(6)-C(7) 111.20(10) C(13)-C(14)-C(15) 119.82(12) N(1)-C(2)-N(3) 118.68(10) N(1)-C(6)-C(19) 111.13(10) C(14)-C(15)-C(16) 120.42(12) N(3)-C(4)-C(5) 105.16(8) C(7)-C(6)-C(19) 112.36(11) C(11)-C(16)-C(15) 120.36(11) N(3)-C(4)-C(8) 106.44(8) O(9)-C(8)-O(20) 123.58(11) C(5)-C(17)-C(18) 110.50(9) N(3)-C(4)-C(11) 113.44(9) O(9)-C(8)-C(4) 111.56(9) C(5)-C(17)-C(21) 114.15(9) C(5)-C(4)-C(8) 108.57(8) O(20)-C(8)-C(4) 124.85(10) C(18)-C(17)-C(21) 109.42(10) C(5)-C(4)-C(11) 116.10(9) C(4)-C(11)-C(12) 120.10(10)

Methyl 1,5-diisopropyl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 26. According to General Procedure I, reaction between benzhydrylamine 25 (733 mg, 4.0 mmol), isobutyraldehyde 18 (288 mg, 4.0 mmol) and isocyanoacetate 23 (330 mg, 1.84 mmol), followed by column chromatography (PE:EtOAc:Et3N = 10:1:0.01, gradient), afforded 26 (99

mg, 13%) as a 66:34 mixture of diastereomers as a colourless oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.47 (m, 2H), 7.35–6.95 (m, 15H + 11 H), 6.88 (s, 1H), 6.79 (s, 1H), 6.72 (m, 2H), 5.57 (s, 1H), 5.55 (s, 1H), 4.34 (d, J = 1.5 Hz, 1H), 3.78 (d, J = 1.8 Hz, 1H), 3.60 (s, 3H), 3.55 (s, 3H), 2.49 (m, 1H), 1.68 (m, 1H), 1.08 (d, J = 7.2 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 4.5 Hz, 3H), 0.48 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 175.1 (C), 173.1 (C), 155.6 (CH), 154.9 (CH), 145.4 (C), 139.9 (C), 139.5 (C), 139.5 (C), 139.1 (C), 137.7 (C), 129.28 (2×CH), 129.25 (2×CH), 129.2 (2×CH), 129.0 (2×CH), 128.9 (2×CH), 128.5 (2×CH), 128.4 (2×CH), 128.31 (CH), 128.29 (2×CH), 128.2 (2×CH), 128.1 (2×CH), 128.0 (CH), 127.91 (CH), 127.85 (CH), 127.88 (CH), 127.85 (2×CH), 127.8 (CH), 126.9 (2×CH), 85.1 (C), 82.8 (C), 74.3 (CH), 68.8 (CH), 65.74 (CH), 65.68 (CH), 53.2 (CH3), 52.9 (CH3), 30.2 (CH), 29.2 (CH), 23.1 (CH3), 22.9 (CH3), 16.9 (CH3), 16.2 (CH3); IR (neat): 2961 (m), 1726 (s), 1595 (s), 1221 (s).

Methyl 1-benzhydryl-5-isopropyl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 28. According to General Procedure I, reaction between p-methoxybenzylamine 27 (274 mg, 2.0 mmol), isobutyraldehyde 18 (144 mg, 2.0 mmol) and isocyanoacetate 23 (191 mg, 1.1 mmol), followed by column chromatography, afforded 28 (292 mg, 73%) as a 76:24 mixture of

diastereomers as an orange oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.45 (d, J = 6.9 Hz, 2H), 7.35 (d, J = 7.2 Hz, 2H), 7.25–7.12 (m, 3H + 3H), 7.09 (d, J = 8.6 Hz, 2H), 7.02 (s, 1H), 7.01 (s, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.72 (d, J = 8.6 Hz, 2H), 6.53 (d, J = 8.6 Hz, 2H), 4.45 (d, J = 14.9 Hz, 1H), 4.38 (d, J = 15.0 Hz, 1H), 4.26 (d, J = 1.4 Hz, 1H), 4.14 (d, J = 414.9 Hz, 1H), 4.02 (d, J = 15.0 Hz, 1H), 3.69 (s, 3H), 3.64 (d, J = 2.0 Hz, 1H), 3.61 (s, 3H), 3.58 (s, 3H), 3.53 (s, 3H), 2.43 (m, 1H), 1.55 (m, 1H), 1.00 (d, J = 7.3 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 7.4 Hz, 3H), 0.38 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 174.2 (C), 172.3 (C), 158.8 (C), 158.6 (C),

N

N

PhMeO2C

PhPh

N

N

PhMeO2C

PMB

Chapter 2

26

156.3 (CH), 156.0 (CH), 144.5 (C), 137.1 (C), 128.6 (2×CH), 128.3 (2×CH), 128.0 (C), 127.8 (C), 127.5 (2×CH), 127.4 (2×CH), 127.2 (2×CH), 127.0 (2×CH), 126.9 (CH), 126.0 (CH), 113.7 (2×CH), 113.5 (2×CH), 83.7 (C), 82.0 (C), 72.3 (CH), 67.5 (CH), 54.8 (CH3), 54.7 (CH3), 52.4 (CH3), 52.0 (CH3), 50.5 (CH2), 50.4 (CH2), 29.3 (CH), 28.4 (CH), 22.3 (CH3), 22.1 (CH3), 16.0 (CH3), 15.3 (CH3); IR (neat): 1726 (s), 1678 (m), 1599 (s), 1512 (s), 1462 (m), 1446 (m), 1246 (s), 1177 (s).

Methyl 5-isopropyl-1,4-diphenyl-4,5-dihydro-1H-imidazole-4-carboxylate 30. According to General Procedure I, reaction between aniline 29 (186 mg, 2.0 mmol), isobutyraldehyde 18 (144 mg, 2.0 mmol) and isocyanoacetate 23 (98 mg, 0.56 mmol), followed by column chromatography, afforded trans-30 (70 mg, 39%) and cis-30 (25 mg, 14%) as yellow oils. trans-

30: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.49 (d, J = 7.4 Hz, 2H), 7.49 (s, 1H), 7.30–7.19 (m, 5H), 7.15 (d, J = 7.9 Hz, 2H), 7.00 (t, J = 7.0 Hz, 1H), 5.30 (d, J = 1.6 Hz, 1H), 3.57 (s, 3H), 1.54 (m, 1H), 0.61 (d, J = 7.3 Hz, 3H), 0.40 (d, J = 6.7 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 174.7 (C), 152.8 (CH), 140.6 (C), 137.2 (C), 129.4 (2×CH), 128.7 (2×CH), 128.1 (CH), 128.0 (2×CH), 124.3 (CH), 120.3 (2×CH), 84.1 (C), 68.5 (CH), 53.5 (CH3), 30.7 (CH), 23.0 (CH3), 16.0 (CH3); IR: 1723 (s), 1589 (s), 1609 (s), 1495 (m), 1210 (s); cis-30: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.62 (d, J = 7.3 Hz, 2H), 7.47 (s, 1H), 7.29–7.17 (m, 5H), 6.96–6.93 (m, 3H), 4.66 (d, J = 2.0 Hz, 1H), 3.69 (s, 3H), 4.56 (m, 1H), 0.86 (d, 6.8 Hz, 3H), 0.78 (d, J = 7.2 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 172.5 (C), 152.0 (CH), 144.4 (C), 140.6 (C), 129.9 (2×CH), 128.7 (2×CH), 128.2 (CH), 126.5 (2×CH), 124.0 (CH), 119.8 (2×CH), 81.8 (C), 73.8 (CH), 53.0 (CH3), 31.4 (CH), 22.5 (CH3), 17.0 (CH3); IR (neat): 1728 (s), 1592 (s), 1503 (s), 1249 (m), 1209 (m).

Methyl 5-isopropyl-1-(4-methoxybenzyl)-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 32. According to General Procedure I, reaction between isopropylamine 17 (236 mg, 4.0 mmol), p-methoxybenzaldehyde 31 (545 mg, 4.0 mmol) and isocyanoacetate 23 (322 mg, 1.84 mmol), followed by column chromatography, afforded 32 (479 mg, 77%) as a 70:30

mixture of diastereomers as a colourless oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.65 (d, J = 7.2 Hz, 2H), 7.33 (s, 1H), 7.32–6.81 (m, 7H + 8H), 6.48 (br s, 2H), 5.46 (s, 1H), 4.86 (s, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.61 (s, 1H), 3.16 (s, 1H), 3.11 (m, 1H), 3.04 (m, 1H), 1.22 (d, J = 6.9 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 174.8 (C), 171.8 (C), 160.0 (C), 159.2 (C), 154.3 (CH), 153.5 (CH), 144.4 (C), 138.2 (C), 130.1 (C), 128.8 (C), 128.5 (2×CH), 127.8 (2×CH + 2×CH), 127.6 (CH), 127.2 (2×CH + 4×CH), 127.1 (CH), 114.2 (2×CH), 113.5 (2×CH), 85.1 (C), 84.4 (C), 73.1 (CH), 68.9 (CH), 55.6 (CH3), 55.5 (CH3), 53.3 (CH3), 52.3 (CH3), 46.5 (CH + CH), 22.2 (CH3), 22.2 (CH3), 21.7 (CH3 + CH3); IR (neat): 2971 (m), 1726 (s), 1595 (s), 1578 (s), 1512 (s), 1246 (s).

Methyl 1-isopropyl-5-(4-methoxyphenyl)-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 33. According to General Procedure I, reaction between p-methoxybenzylamine 27 (274 mg, 2.0 mmol), p-methoxybenzaldehyde 31 (272 mg, 2.0 mmol) and isocyanoacetate 23 (150 mg, 0.86 mmol), followed by column chromatography, afforded 33 (333 mg, 90%)

as a 55:45 mixture of diastereomers as a colourless oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.54 (m, 2H), 7.27 (s, 1H), 7.24–6.62 (m, 11H + 12H), 6.48 (m, 2H), 5.20 (s, 1H), 4.65 (s, 1H), 4.21 (dd, J = 14.1, 14.0 Hz, 2H), 3.70 (s, 3H), 3.68 (s, 3H), 3.67 (dd, J = 14.6, 10.6 Hz, 2H), 3.63 (s, 3H), 3.60 (s, 3H), 3.57 (s, 3H), 3.13 (s, 3H); 13C NMR (101 MHz): δ (ppm) 173.8 (C), 171.0 (C), 159.4 (C), 159.0 (C), 158.9 (C), 158.7 (C), 156.3 (CH), 155.4 (CH), 143.2 (C), 138.3 (C), 129.2 (2×CH + 2×CH), 129.1 (2×CH), 128.9 (2×CH), 128.1 (C), 127.9 (CH), 127.6 (C), 127.4 (C), 127.3 (2×CH + 2×CH), 127.0 (C), 126.7 (CH), 126.5 (2×CH), 126.4 (2×CH), 113.9 (2×CH), 113.8 (2×CH), 113.5 (2×CH), 113.0 (2×CH), 84.9 (C), 83.9 (C), 72.0 (CH), 68.6 (CH), 54.98 (CH3 + CH3), 54.96 (CH3), 54.8 (CH3), 52.6 (CH3), 51.7 (CH3), 48.4 (CH2), 47.9 (CH2); IR (neat): 1728 (s), 1610 (s), 1512 (s), 1248 (s).

N

N

PhMeO2C

MeO

N

N

PhMeO2C

PMBMeO

N

N

PhMeO2C

Ph


27

Methyl 1-isopropyl-5-(5-methylfuran-2-yl)-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 35. According to General Procedure I, reaction between isopropylamine 17 (236 mg, 4.0 mmol), 5-methylfurfural 34 (432 mg, 4.0 mmol) and isocyanoacetate 23 (365 mg, 2.05 mmol), followed by column chromatography afforded 35 (359 mg, 54%) as a 76:24 mixture of

diastereomers as an orange oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.74 (m, 2H), 7.39–7.10 (m, 6H + 4H), 6.26 (d, J = 3.0 Hz, 1H), 5.97 (d, J = 2.9 Hz, 1H), 5.94 (d, J = 3.0 Hz, 1H), 5.67 (s, 1H), 5.59 (d, J = 2.8 Hz, 1H), 4.98 (s, 1H), 3.74 (s, 3H), 3.48 (s, 3H), 3.31 (m, 1H + 1H), 2.31 (s, 3H), 1.91 (s, 3H), 1.29 (d, J = 6.7 Hz, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.5 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 174.4 (C), 170.9 (C), 153.9 (CH), 153.7 (CH), 152.8 (C), 152.6 (C), 149.5 (C), 148.2 (C), 144.0 (C), 138.9 (C), 128.6 (CH), 127.9 (CH), 127.6 (2×CH), 127.3 (2×CH), 127.0 (2×CH), 126.8 (2×CH), 111.3 (CH), 110.4 (CH), 107.0 (CH), 105.9 (CH), 83.9 (C), 83.1 (C), 67.5 (CH), 63.0 (CH), 53.4 (CH3), 52.7 (CH3), 47.1 (CH), 46.9 (CH), 22.3 (CH3), 22.0 (CH3), 21.9 (CH3), 21.9 (CH3), 14.0 (CH3), 13.5 (CH3); IR (KBr): 2967 (s), 2949 (s), 1721 (s), 1593 (s), 1576 (s), 1287 (s), 1260 (s), 1231 (s), 1211 (s).

Methyl 1-isopropyl-5-(5-methylfuran-2-yl)-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 35. According to General Procedure I, reaction between p-methoxybenzylamine 27 (274 mg, 2.0 mmol), 5-methylfurfural 34 (220 mg, 2.0 mmol) and isocyanoacetate 23 (163 mg, 0.93 mmol), followed by column chromatography afforded 35 (343 mg, 91%) as a 70:30

mixture of diastereomers as an orange oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.50 (d, J = 7.4 Hz, 2H), 7.18–6.93 (m, 6H + 4H), 6.93 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 2H), 6.08 (d, J = 3.0 Hz, 1H), 5.81 (m, 1H), 5.77 (d, J = 3.0 Hz, 1H), 5.44 (m, 1H), 5.31 (s, 1H), 4.64 (s, 1H), 4.21 (d, J = 14.8 Hz, 1H), 4.17 (d, J = 14.8 Hz, 1H), 3.73 (d, J = 14.8 Hz, 1H), 3.73 (d, J = 14.8 Hz, 1H), 3.65 (s, 3H), 3.60 (s, 3H), 3.55 (s, 3H), 3.32 (s, 3H), 2.14 (s, 3H), 1.75 (s, 3H); 13C NMR (101 MHz): δ (ppm) 173.5 (C), 171.2 (C), 159.1 (C)), 159.1 (C), 155.8 (CH), 155.6 (CH), 152.7 (C), 152.4 (C), 147.8 (C), 146.6 (C), 142.9 (C), 138.4 (C), 129.1 (2×CH), 129.1 (2×CH), 128.1 (2×CH), 128.0 (C), 127.7 (C), 127.5 (CH), 127.3 (2×CH), 126.9 (2×CH), 126.4 (CH), 126.3 (2×CH), 114.02 (2×CH), 113.98 (2×CH), 111.8 (CH), 110.8 (CH), 106.5 (CH), 105.4 (CH), 84.1 (C), 83.6 (C), 67.0 (CH), 63.3 (CH), 55.2 (CH3), 55.1 (CH3), 52.9 (CH3), 52.3 (CH3), 48.6 (CH2), 48.4 (CH2), 13.6 (CH3), 13.1 (CH3); IR (neat): 1728 (s), 1597 (s), 1512 (s), 1248 (s), 1175 (s).

Methyl 1-isopropyl-4-phenyl-5-(pyridin-2-yl)-4,5-dihydro-1H-imidazole-4-carboxylate 38. According to General Procedure I, reaction between isopropylamine 17 (236 mg, 4.0 mmol), pyridine-5-carboxaldehyde 37 (428 mg, 4.0 mmol) and isocyanoacetate 23 (357 mg, 2.04 mmol), followed by column chromatography, afforded 38 (456 mg, 71%) as a 84:16 mixture of

diastereomers as a yellow solid. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.62 (d, J = 4.6 Hz, 1H), 8.31 (d, J = 4.6 Hz, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.68 (m, 2H), 7.40–7.18 (m, 2H + 6H), 7.02–6.74 (m, 7H), 5.83 (s, 1H), 5.17 (s, 1H), 3.73 (s, 3H), 3.27 (m, 1H), 3.20 (m, 1H), 3.17 (s, 3H), 1.30 (d, J = 6.7 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 173.6 (C), 171.3 (C), 159.0 (C), 157.5 (C), 154.1 (CH), 153.7 (CH), 149.2 (CH), 148.6 (CH), 143.6 (C), 138.0 (C), 136.4 (CH), 135.5 (CH), 128.7 (2×CH), 127.4 (CH), 127.3 (2×CH), 126.9 (2×CH), 126.8 (2×CH), 126.6 (CH), 123.2 (CH), 122.8 (CH), 121.9 (CH), 121.9 (CH), 85.0 (C), 84.8 (C), 74.3 (CH), 69.3 (CH), 53.0 (CH3), 51.9 (CH3), 47.0 (CH), 46.9 (CH), 21.8 (CH3), 21.6 (CH3), 21.6 (CH3), 21.6 (CH3); IR (neat): 2972 (m), 1728 (s), 1591 (s), 1578 (s), 1223 (s). Slow crystallisation from hexanes/EtOAc (10:1) afforded the pure trans-38 as white crystals. Mp 112.9–114.5 oC; 1H NMR (250 MHz, CDCl3): δ (ppm) 8.40 (m, 1H), 7.45 (s, 1H), 7.37–7.29 (m, 1H), 7.13–6.85 (m, 7H), 5.92 (s, 1H), 3.82 (s, 3H), 3.37 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H); 13C NMR (63 MHz): δ (ppm) 173.8 (C), 157.7 (C), 154.1 (CH), 148.7 (CH), 138.2 (C), 135.4 (CH), 127.3 (2×CH), 127.0 (2×CH), 126.6 (CH), 123.2 (CH), 121.9 (CH), 85.0 (C), 69.4 (CH), 53.0 (CH3), 47.0 (CH), 21.8 (CH3), 21.7 (CH3); IR (KBr): 2971 (m), 1728 (s), 1589 (s), 1225 (s).

N

N

PhMeO2C

PMBO

N

N

PhMeO2C

N

N

N

PhMeO2C

O

Chapter 2

28

Methyl 1-isopropyl-4-phenyl-5-(pyridin-2-yl)-4,5-dihydro-1H-imidazole-4-carboxylate 41. According to General Procedure I, reaction between furfurylamine 39 (194 mg, 2.0 mmol), ethyl-trans-4-oxo-butenoate 40 (256 mg, 2.0 mmol) and isocyanoacetate 23 (167 mg, 0.95 mmol), followed by column chromatography, afforded trans-41 (115 mg, 32%)

and cis-41 (56 mg, 15%) as orange oils. trans-41: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.36 (m, 1H), 7.29–7.22 (m, 5H), 7.14–7.11 (m, 2H), 6.31 (d, J = 3.1, 1.9 Hz, 1H), 6.20 (d, J = 3.1 Hz, 1H), 5.97 (dd, J = 15.7, 8.4 Hz, 1H), 5.87 (d, J = 15.7 Hz, 1H), 4.78 (d, J = 8.4 Hz, 1H), 4.34 (d, J = 15.9 Hz, 1H), 4.07 (m, 2H), 4.01 (d, J = 15.9 Hz, 1H), 3.73 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 173.0 (C), 165.1 (C), 156.4 (CH), 149.0 (C), 142.9 (CH), 142.5 (CH), 136.3 (C), 128.3 (2×CH), 127.9 (CH), 126.4 (2×CH), 125.0 (CH), 110.4 (CH), 109.0 (CH), 84.1 (C), 65.8 (CH), 60.3 (CH2), 53.0 (CH3), 42.0 (CH2), 14.0 (CH3); IR (neat): 1732 (s), 1672 (m), 1601 (m), 1254 (s), 1235 (s), 1181 (s); cis-41: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.48 (m, 2H), 7.34–7.24 (m, 4H), 7.24 (s, 1H), 7.02 (dd, J = 15.6, 8.6 Hz, 1H), 6.24 (dd, J = 3.2, 1.9 Hz, 1H), 6.11 (d, J = 3.1 Hz, 1H), 6.02 (dd, J = 15.6, 0.7 Hz, 1H), 4.35 (d, J = 15.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.16 (d, J = 8.6 Hz, 1H), 4.05 (d, J = 15.9 Hz, 1H), 3.65 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 170.8 (C), 165.4 (C), 156.7 (CH), 149.0 (C), 143.0 (CH), 142.7 (CH), 142.2 (C), 128.4 (2×CH), 127.8 (CH), 126.1 (2×CH), 125.3 (CH), 110.3 (CH), 109.1 (CH), 84.3 (C), 70.6 (CH), 60.7 (CH2), 52.6 (CH3), 42.2 (CH2), 14.2 (CH3); IR (neat): 1728 (s), 1669 (s), 1599 (s), 1256 (s), 1233 (s), 1181 (s).

Methyl 4-phenyl-4,5-dihydrooxazole-4-carboxylate 42a. According to General Procedure I, reaction between NH3 (2M in MeOH, 2.3 ml, 4.6 mmol), p-formaldehyde (60 mg, 2.0 mmol) and isocyanoacetate 23 (175 mg, 1.0 mmol), followed by flash column chromatography

(EtOAc:MeOH:Et3N = 1:0:0.01, gradient), did not afford the expected 2-imidazoline, but the corresponding 2-oxazoline 42a (235 mg, quant.) as a yellow oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.42–7.28 (m, 5H), 7.08 (s, 1H), 5.21 (d, J = 8.9 Hz, 1H), 4.28 (d, J = 8.9 Hz, 1H), 3.77 (s, 3H); 13C NMR (63 MHz, CDCl3): 171.4 (C), 161.0 (CH), 136.2 (C), 128.8 (2×CH), 128.5 (CH), 126.0 (2×CH), 67.8 (C), 64.7 (CH2), 53.5 (CH3); IR (neat): 2956 (s), 1757 (s), 1257 (s), 1214 (s); MS (EI, 70 eV): m/z (%) = 205 (0.5) [M]+, 187 (100), 145 (68).

Methyl 1-isopropyl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 42b. According to General Procedure I, reaction between isopropylamine 17 (118 mg, 2.0 mmol), p-formaldehyde (60 mg, 2.0 mmol) and isocyanoacetate 23 (175 mg, 1.0 mmol), followed by flash column chromatography (EtOAc:MeOH:Et3N = 1:0:0.01, gradient), afforded 42b (173 mg, 70%) as a

yellow oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.40–7.19 (m, 5H), 6.98 (s, 1H), 4.27 (d, J = 9.6 Hz, 1H), 3.63 (s, 3H), 3.53–3.42 (m, 1H), 3.27 (d, J = 9.6 Hz, 1H), 1.15 (d, J = 6.6 Hz, 3H), 1.11 (d, J = 6.6 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 173.9 (C), 154.8 (CH), 143.1 (C), 128.4 (2×CH), 127.3 (CH), 125.4 (2×CH), 79.1 (C), 54.6 (CH2), 52.8 (CH3), 47.6 (CH), 21.14 (CH3), 21.09 (CH3); IR (neat): 2970 (s), 1726 (s), 1593 (s), 1254 (s), 1214 (s); HRMS (EI, 70 eV) calculated for C14H18N2O2 (M+) 246.1368, found 246.1392.

Methyl 1-tert-butyl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 42c. According to General Procedure I, reaction between tert-butylamine (730 mg, 10.0 mmol), p-formaldehyde (300 mg, 10.0 mmol) and isocyanoacetate 23 (1.0 g, 5.7 mmol), followed by flash column chromatography, afforded 42c (1.28 g, 86%) as a yellow oil. 1H NMR (250 MHz, CDCl3): δ

(ppm) 7.39–7.35 (m, 2H), 7.29–7.18 (m, 3H), 7.10 (s, 1H), 4.31 (d, J = 9.7 Hz, 1H), 3.62 (s, 3H), 3.30 (d, J = 9.7 Hz, 1H), 1.18 (s, 9H); 13C NMR (101 MHz, CDCl3): δ (ppm) 174.1 (C), 153.6 (CH), 143.4 (C), 128.5 (2×CH), 127.4 (CH), 125.6 (2×CH), 79.2 (C), 54.3 (CH2), 52.9 (CH3), 52.5 (C), 29.1 (3×CH3); IR (neat) 2972 (s), 1726 (s), 1592 (s), 1258 (s), 1236 (s), 1201 (s); HRMS (EI, 70 eV) calculated for C15H20N2O2 (M+) 286.1893, found 286.1890.

N

N

PhMeO2C

EtO2C O

N

O

PhMeO2C

N

N

PhMeO2C

N

N

PhMeO2C


29

Methyl 1-mesityl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 42d. According to General Procedure I, reaction between 2,4,6-trimethylaniline (270 mg, 2.0 mmol), p-formaldehyde (60 mg, 2.0 mmol) and isocyanoacetate 23 (175 mg, 1.0 mmol), followed by flash column chromatography, afforded 42d (209 mg, 65%) as a yellow oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.76–7.50 (m, 6H), 7.15–7.11 (m, 2H), 4.94 (d, J = 9.8 Hz, 1H), 4.01 (s, 3H), 3.81 (d, J = 9.8 Hz, 1H), 2.52 (s, 3H), 2.50–2.29 (br s, 6H); 13C NMR (63 MHz, CDCl3): δ

(ppm) 173.7 (C), 155.7 (CH), 143.2 (2×C), 137.8 (2×C), 133.3 (C), 129.3 (2×CH), 128.6 (2×CH), 127.5 (CH), 125.5 (2×CH), 80.4 (C), 58.7 (CH2), 53.0 (CH3), 20.8 (CH3), 17.8 (2×CH3); IR (neat): 2951 (m), 2923 (m), 1729 (s), 1600 (s), 1576 (s), 1488 (s), 1263 (s), 1217 (s); HRMS (EI, 70 eV) calculated for C20H22N2O2 (M+) 322.1681, found 322.1672.

Methyl 1-benzhydryl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 42e. According to General Procedure I, reaction between benzhydrylamine 25 (366 mg, 2.0 mmol), p-formaldehyde (60 mg, 2.0 mmol) and isocyanoacetate 42 (196 mg, 1.12 mmol), followed by flash column chromatography, afforded 42e (340 mg, 82%) as a yellow oil. 1H NMR (250 MHz,

CDCl3): δ (ppm) 7.34–7.30 (m, 2H), 7.25–7.08 (m, 12H), 7.00–6.85 (m, 1H), 6.82 (s, 1H), 5.32 (s, 1H), 4.24 (d, J = 9.8 Hz, 1H),, 3.59 (s, 3H), 3.19 (d, J = 9.8 Hz, 1H); 13C NMR (63 MHz, CDCl3): δ (ppm) 174.0 (C), 156.4 (CH), 142.8 (C), 139.8 (C), 139.8 (C), 129.3 (2×CH), 129.0 (2×CH), 128.6 (CH), 128.44 (CH), 128.40 (CH), 128.36 (2×CH), 128.3 (2×CH), 128.0 (CH), 127.9 (CH), 126.0 (2×CH), 80.3 (C), 66.4 (CH), 58.6 (CH2), 53.4 (CH3); IR (KBr): 3025 (m), 1721 (s), 1595 (m), 1258 (s), 706 (s); HRMS (EI, 70 eV) calculated for C24H22N2O2 (M+) 370.1681, found 370.1691.

Methyl 5-isopropyl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 42f. According to General Procedure I, reaction between NH3 (2M in MeOH, 2.3 ml, 4.6 mmol), i-butyraldehyde 18 (154 mg, 2.1 mmol) and isocyanoacetate 23 (192 mg, 1.1 mmol), followed by flash column

chromatography, afforded 42f (206 mg, 76%) as a 68:32 mixture of diastereomers as a yellow oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.60–7.46 (m, 2H), 7.45–7.33 (m, 2H), 7.30–7.10 (m, 4H + 4H), 6.2 (br s, 1H + 1H), 4.53 (d, J = 3.2 Hz, 1H), 4.09 (d, J = 2.2 Hz, 1H), 3.64 (s, 3H), 3.62 (s, 3H), 2.45–2.35 (m, 1H), 1.55–1.40 (m, 1H), 1.01 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 0.71 (d, J = 6.6 Hz, 3H), 0.35 (d, J = 6.6 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 175.1 (C), 172.8 (C), 154.1 (CH), 153.3 (CH), 144.1 (C), 136.9 (C), 128.7 (CH), 128.4 (2×CH), 128.1 (CH), 128.0 (CH), 127.5 (2×CH), 126.3 (CH), 78.7 (C), 78.6 (CH), 76.6 (C), 71.7 (CH), 53.3 (CH3), 52.9 (CH3), 29.6 (CH), 29.1 (CH), 22.0 (CH3), 21.8 (CH3), 16.1 (CH3), 16.0 (CH3); IR (KBr): 3136 (m), 2938 (m), 1728 (s), 1221 (s); HRMS (EI, 70 eV) calculated for C14H18N2O2 (M+) 246.1368, found 246.1352.

(trans)-Methyl 1-tert-butyl-5-isopropyl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 42g. According to General Procedure I, reaction between tert-butylamine (146 mg, 2.0 mmol), i-butyraldehyde 18 (144 mg, 2.0 mmol) and isocyanoacetate 23 (190 mg, 1.09 mmol), followed by flash column chromatography, afforded trans-42g (59 mg, 21%) as a sticky yellow solid. 1H

NMR (250 MHz, CDCl3): δ (ppm) 7.56–7.44 (m, 2H), 7.31–7.17 (m, 4H), 4.50 (d, J = 2.1 Hz, 1H), 4.48 (s, 3H), 1.58–1.49 (m, 1H), 1.27 (s, 9H), 0.74 (d, J = 7.2 Hz, 3H), 0.40 (d, J = 6.9 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 175.2 (C), 155.3 (CH), 137.5 (C), 128.2 (2×CH), 127.9 (2×CH), 127.5 (CH), 83.8 (C), 66.7 (CH), 53.4 (C), 52.7 (CH3), 30.7 (3×CH3), 29.7 (CH), 20.0 (CH3), 17.0 (CH3); IR (neat): 2956 (m), 2914 (m), 2850 (m), 1745 (s), 1667 (s), 1217 (s); HRMS (EI, 70 eV) calculated for C18H26N2O2 (M+) 302.1994, found 302.1998.

Methyl 5-tert-butyl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 42i. According to General Procedure I, reaction between NH3 (2M in MeOH, 2.0 ml, 4.0 mmol), pivaldehyde (172 mg, 2.0 mmol) and isocyanoacetate 23 (175 mg, 1.0 mmol), followed by flash column chromatography, afforded 42i (146 mg, 56%) as a 78:22 mixture of diastereomers as a white solid.

1H NMR (250 MHz, CDCl3): δ (ppm) 7.61–7.56 (m, 2H), 7.49–7.36 (m, 2H), 7.30–7.16 (m, 4H + 4H), 4.43 (d, J =

N

N

PhMeO2C

N

N

PhMeO2C

PhPh

N

HN

PhMeO2C

N

HN

PhMeO2C

N

N

PhMeO2C

Chapter 2

30

0.9 Hz, 1H), 4.02 (s, 1H), 3.67 (s, 3H), 3.65 (s, 3H), 0.99 (s, 9H), 0.60 (s, 9H); 13C NMR (63 MHz, CDCl3): δ (ppm) 174.8 (C), 172.7 (C), 153.1 (CH), 151.9 (CH), 144.3 (C), 136.3 (C), 128.3 (2×CH), 128.00 (2×CH), 127.97 (2×CH), 127.8 (2×CH), 127.4 (CH), 126.8 (CH), 84.1 (CH), 78.5 (C), 74.9 (CH), 52.9 (CH3), 52.5 (CH3), 34.8 (C), 34.5 (C), 27.2 (3×CH3), 27.1 (3×CH3) (one quarternary C of minor diastereomer remained undetectable); IR (neat): 3186 (s, br), 2954 (s), 1732 (s), 1597 (s), 1254 (s); HRMS (EI, 70 eV) calculated for C15H20N2O2 (M+) 260.1525, found 260.1523.

(trans)-Methyl 5-tert-butyl-4-phenyl-4,5-dihydrooxazole-4-carboxylate 42k. According to General Procedure I, reaction between tert-butylamine (146 mg, 2.0 mmol), pivaldehyde (172 mg, 2.0 mmol) and isocyanoacetate 23 (175 mg, 1.0 mmol), followed by flash column chromatography, did not afford the expected 2-imidazoline, but the corresponding 2-oxazoline 42k (26 mg, 10%) as

a single diastereomer (trans) as a yellow oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.83 (d, J = 7.2 Hz, 2H), 7.44–7.37 (m, 3H), 7.30–7.25 (m, 1H), 4.38 (s, 1H), 4.07 (s, 3H), 1.06 (s, 9H); 13C NMR (63 MHz, CDCl3): 154.4 (C), 131.1 (C), 129.1 (CH), 128.5 (2×CH), 126.5 (CH), 125.0 (2×CH), 75.8 (CH), 60.4 (C), 60.1 (CH3), 36.0 (C), 25.3 (CH3); IR (neat): 2957 (s), 1741 (s), 1713 (s), 1250 (s), 1079 (s); HRMS (EI, 70 eV) calculated for C15H19NO3 (M+) 261.1365, found 261.1383.

(trans)-Methyl 5-mesityl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 42n. According to General Procedure I, reaction between NH3 (2M in MeOH, 2.0 ml, 4.0 mmol), mesitaldehyde (296 mg, 2.0 mmol) and isocyanoacetate 23 (175 mg, 1.0 mmol), followed by precipitation from Et2O and PE, afforded trans-42n (216 mg, 67%) as a white solid. Mp = 222–225 ºC; 1H NMR (250 MHz, CDCl3): δ (ppm) 7.18–7.09 (m, 3H), 6.98–6.93 (m, 3H), 6.71 (s, 1H), 6.35 (s, 1H), 6.34 (s,

1H), 3.62 (s, 3H), 2.58 (s, 3H), 2.05 (s, 3H), 1.65 (s, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 175.1 (C), 152.3 (CH), 138.4 (C), 137.8 (C), 137.7 (C), 137.0 (C), 131.5 (C), 130.8 (CH), 129.0 (CH), 127.0 (2×CH), 126.9 (CH), 126.8 (2×CH), 81.0 (C)*, 64.5 (CH)*, 53.2 (CH3), 21.4 (CH3), 20.6 (CH3), 20.3 (CH3), The * labeled signals could only be found using gs-HMBC and gs-HMQC measurements; IR (neat): 3056 (s, br), 2949 (s), 2916 (s), 2853 (m), 1732 (s), 1597 (s), 1447 (s), 1232 (s); HRMS (EI, 70 eV) calculated for C20H22N2O2 (M+) 322.1681, found 322.1666.

(trans)-Methyl 1-tert-butyl-5-mesityl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 42p. According to General Procedure I, reaction between tert-butylamine (146 mg, 2.0 mmol), mesitaldehyde (296 mg, 2.0 mmol) and isocyanoacetate 23 (175 mg, 1.0 mmol), followed by flash column chromatography, afforded trans-42p (58 mg, 15%) as a single diastereomer as a sticky white solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.27 (s, 1H), 7.15 (d, J = 5.9 Hz, 2H),

7.01–6.95 (m, 3H), 6.69 (s, 1H), 6.32 (s, 1H), 6.24 (br s, 1H), 3.66 (s, 3H), 2.63 (s, 3H), 2.08 (s, 3H), 1.80 (s, 3H), 1.18 (s, 9H); 13C NMR (63 MHz, CDCl3): δ (ppm): 175.0 (C), 153.9 (CH), 138.3 (C), 138.0 (C), 136.3 (C), 136.2 (C), 133.6 (C), 130.7 (CH), 128.9 (CH), 126.7 (2×CH), 126.5 (CH), 125.7 (2×CH), 85.5 (C), 61.4 (CH), 54.2 (C), 53.1 (CH3), 29.2 (3×CH3), 21.3 (CH3), 20.8 (CH3), 20.6 (CH3); IR (neat): 2974 (s), 1723 (s), 1597 (s), 1237 (s), 1212 (s), 1197 (s); HRMS (EI, 70 eV) calculated for C24H30N2O2 (M+) 378.2307, found 378.2319.

Methyl 1-benzhydryl-5-mesityl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 42r. According to General Procedure I, reaction between benzhydrylamine 25 (366 mg, 2.0 mmol), mesitaldehyde (296 mg, 2.0 mmol) and isocyanoacetate 23 (180 mg, 1.03 mmol), followed by flash column chromatography, afforded 42r (84 mg, 17%) as a 74:26 mixture of diastereomers as a yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.65–7.63 (m, 2H), 7.42–6.94 (m, 15H +

13H), 6.90 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.74 (s, 1H), 6.66 (s, 1H), 6.48 (s, 1H), 6.20 (s, 1H), 5.33 (s, 1H), 4.99 (s, 1H), 4.94 (s, 1H), 3.67 (s, 3H), 3.33 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 2.14 (s, 3H), 1.92 (s, 3H), 1.73 (s, 3H), 1.71 (s, 3H); 13C NMR (101 MHz, CDCl3): δ (ppm) 174.9 (C), 171.5 (C), 153.1 (CH), 152.9 (CH), 144.4 (C), 141.0 (C), 139.3 (C), 139.2 (C), 139.1 (C), 138.9 (C), 138.7 (C), 138.4 (C), 138.3 (C), 138.2 (C), 137.3 (C),

N

O

PhMeO2C

N

N

PhMeO2C

N

HN

PhMeO2C

N

N

PhMeO2C

PhPh


31

137.20 (C), 137.16 (C), 131.3 (CH), 130.6 (CH), 130.4 (C), 129.5 (CH), 129.4 (CH + CH), 129.2 (CH), 129.1 (CH), 128.90 (CH), 128.87 (CH), 128.86 (CH), 128.69 (CH), 128.67 (CH), 128.5 (CH), 128.30 (CH), 128.25 (CH), 127.9 (CH + CH), 127.8 (CH), 127.58 (CH), 127.56 (CH), 127.4 (CH), 127.33 (CH), 127.30 (CH + CH), 127.1 (CH), 126.8 (CH + CH), 126.7 (CH), 126.0 (CH), 124.9 (CH), 84.4 (C), 84.0 (C), 67.4 (CH), 64.1 (CH), 63.7 (CH), 63.3 (CH), 53.2 (CH3), 51.9 (CH3), 21.3 (CH3), 20.9 (CH3), 20.7 (2×CH3), 20.7 (CH3), 20.4 (CH3), the assignments of the several signals was confirmed using gs-HMBC and gs-HMQC measurements. Due to the crowded aromatic region, not all 34 different aromatic CH signals could be assigned; IR (neat): 3029 (m), 2950 (m), 1726 (s), 1594 (s), 1576 (s), 1493 (s), 1452 (s), 1225 (s), 1179 (s); HRMS (EI, 70 eV) calculated for C33H32N2O2 (M+) 488.2464, found 488.2459.


[1] a) Peddibhotla, S.; Jayakumar, S.; Tepe, J. J. Org. Lett. 2002, 4, 3533−3535. b) Sharma, V.; Tepe, J. J. Org. Lett. 2005, 7, 5091–5094.

[2] Meyer, R.; Schöllkopf, U.; Böhme, P. Liebigs Ann. Chem. 1977, 1183–1193. [3] a) van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977, 42, 1153−1159. b) Sisko, J.;

Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org. Chem. 2000, 65, 1516−1524. [4] Hantke, K.; Schöllkopf, U.; Hausberg, H.-H. Liebigs Ann. Chem. 1975, 1531–1537. [5] Especially the parent α-isocyanoacetonitrile is very unstable. See also reference 4. [6] a) Hagedorn, I.; Eholzer, U.; Etling, H. Chem. Ber. 1965, 98, 193–201. b) Schöllkopf, U.; Chem. Ber. 1973,

106, 3382–3390. c) Ferris, J. P.; Trimmer, R. W. J. Org. Chem. 1976, 41, 13–19. d) Vedejs, E.; Barda, D. A. Org. Lett. 2000, 2, 1033–1035.

[7] See for example: Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463. [8] a) Sun, X.; Janvier, P.; Zhao, G.; Bienaymé, H.; Zhu, J. Org. Lett. 2001, 3, 877–880. b) Janvier, P.; Sun, X.;

Bienhaymé, H.; Zhu, J. J. Am. Chem. Soc. 2002, 124, 2560–2567. c) Janvier, P.; Bienaymé, H.; Zhu, J. Angew. Chem. Int. Ed. 2002, 41, 4291–4294. d) Fayol, A.; Zhu, J. Org. Lett. 2004, 6, 115–118. e) Tron, G. C.; Zhu, J. Synlett 2005, 532–534. f) Fayol, A.; Housseman, C.; Sun, X.; Janvier, P.; Bienaymé, H.; Zhu, J. Synthesis 2005, 161–165. g) For a microreview on recent isocyanide based MCRs and post-transformations, see: Zhu, J. Eur. J. Org. Chem. 2003, 1133–1144.

[9] a) Zhao, G.; Sun, X.; Bienaymé, H.; Zhu, J. J. Am. Chem. Soc. 2001, 123, 6700–6701. b) Janvier, P.; Bois-Choussy, M.; Bienaymé, H.; Zhu, J. Angew. Chem. Int. Ed. 2003, 42, 811–814.

[10] Schöllkopf reported that reactions between the isocyanoacetate 15 and imines at 10 mmol scale in methanol were usually complete after 3 h. See also reference 2.

[11] a) Lehnhoff, S.; Goebel, M.; Karl, R. M.; Klösel, R.; Ugi, I. Angew. Chem. 1995, 107, 1208−1211. b) Cheng, J.-F.; Chen, M.; Arrhenius, T.; Nadzan, A. Tetrahedron Lett. 2002, 43, 6293−6296. c) Bradley, H.; Fitzpatrick, G.; Glass, W. K.; Kunz, H.; Murphy, P. V. Org. Lett. 2001, 3, 2629−2632.

[12] Cristau, P.; Vors, J.-P.; Zhu, J. Org. Lett. 2001, 3, 4079−4082. [13] Creedon, S. M.; Crowley, H. K.; McCarthy, D. G. J. Chem. Soc., Perkin Trans. 1 1998, 1015–1017. [14] Hoppe, D.; Schöllkopf, U. Angew. Chem. Int. Ed. 1970, 9, 300–301.

Chapter 3

Multicomponent Synthesis of 2H-2-Imidazolines

Scope Broadening

Robin S. Bon, Nanda E. Sprenkels, Bart van Vliet, Chongen Hong, Rob F. Schmitz, Frans J.J. de Kanter, Marcel Swart, F. Matthias

Bickelhaupt, André R. Groenhof, Marinus B. Groen, Romano V.A. Orru

Department of Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands


J. Org. Chem. 2005, 70, 3542–3553

Abstract: By using isocyanides other than isocyanoacetates, the scope of the multicomponent synthesis of 2H-2-imidazolines was broadened significantly. The limitations of the methodology seem to be determined by the reactivity of the isocyanide rather than by the presence of additional functional groups on the imine. The less reactive p-nitrobenzyl isocyanide reacts successfully with amines and aldehydes when a catalytic amount of silver(I) actetate is used. Some of the resulting p-nitrophenyl-substituted 2-imidazolines undergo air oxidation to the corresponding imidazoles. Differences in reactivity of the employed isocyanides are explained with use of DFT calculations. Difficult reactions with ketones instead of aldehydes as the oxo-component in this MCR are promoted by silver(I) acetate as well. Diastereoselectivity of reactions with chiral amine or aldehyde inputs appeared to be solvent dependent.

Chapter 3

34

3.1 Introduction

In the previous chapter, the development of a novel multicomponent synthesis of 2H-2-imidazolines was described. The compatibility of a range of structurally different amines and aldehydes in this MCR was demonstrated, but the reaction seems to be critically dependent on the acidity of the isocyanide α-proton and the steric congestion around the imine carbon. So far, the method proved useful to prepare 4-disubstituted 2H-2-imidazolines. Furthermore, ketones were not tested yet as the oxo-component in the MCR. Finally, no chiral amines or aldehydes have been used. Here, we wish to report an extensive scope study addressing the following issues: (i) Further variation of the isocyanide, amine and aldehyde components. (ii) Synthesis of 4-monosubstituted 2-imidazolines. (iii) The application of ketones instead of aldehydes as the oxo-components in the MCR. (iv) The use of chiral amine or aldehyde inputs.

3.2 MCRs with 9-Isocyanofluorene

The much greater acidity of fluorene 2 relative to diphenylmethane 1 reflects the aromatic stabilization of the cyclopentadienide ring in the fluorene anion. In fact, the measured pKa of fluorene in DMSO (25 ºC) is equal to that of ethyl 2-phenylacetate 3 (Figure 1).1 Therefore, 9-isocyanofluorene 4 (pKa (DMSO, 25 ºC) = 12.3) was believed to be sufficiently acidic to undergo cycloaddition with imines.

CO2Et

NC

4, 12.31, 32.3 2, 22.6 3, 22.6

Figure 1. pKa Values of substituted methylenes and 9-isocyanofluorene, measured in DMSO containing K+ salt at 25 ºC.

The stable, crystalline, almost odourless 4 can be prepared from 9-aminofluorene 5 in 88% following a two step procedure (Scheme 1).

Scheme 1a

NH2

a

98%

b

90%

HN

O

NC

5 6 4 a Reagents and conditions: (a) acetic formic anhydride, DCM, 0 ºC to rt, 1 h; (b) Et3N, POCl3, THF, −78 ºC to 0 ºC, 1 h.

Condensation of 4 with a variety of functionalised amines (aliphatic, benzylic, or furfuryl) and aldehydes (aliphatic, (hetero)aromatic, or α,β-unsaturated) under standard

Multicomponent Synthesis of 2H-2-Imidazolines: Scope Broadening

35

reaction conditions (Na2SO4, DCM, 18 h, rt) provides a range of spiro-2-imidazolines (Table 1). The yields were generally good (up to 91%), but once more, application of benzhydryl amine 7 resulted in an unsatisfying yield (entry 1, 20%). Again, steric factors seem to determine the limitations of this MCR.2

Table 1. Series of 2H-2-imidazolines synthesised from 4 entry amine aldehyde product yielda

1 NH2

Ph Ph

7

O8

N

N

9

PhPh

20%

2 NH2

10

O8

N

N

11

84%

3 NH212

OMe

O8

N

NPMB

13

91%

4 NH

H2N

14

O8

N

N

15

NH

67%

5 NH2

10

O16

OMe

N

N

17

MeO

70%

6

NH212

OMe

O16

OMe

N

NPMB

18

MeO

80%

Chapter 3

36

Table 1. (continued) entry amine aldehyde product yielda

7

NH212

OMe

O19

MeO

N

NPMB

20

OMe

80%

8 NH212

OMe

O

O

21

N

NPMB

22

O

60%

9 NH212

OMe

O

O

23

N

NPMB

24

O

61%

10 OH2N

25

O

CO2Et

26

N

N

27

OEtO2C

67%

a Isolated yields are reported.

To synthesise 2-imidazolines susceptible to further manipulation, amines and aldehydes

containing additional functional groups were tested in our MCR. (Table 2). Although application of an α,β-unsaturated aldehyde proved successful before (see Table 1, entry 10 and Chapter 2, Table 3, entry 9), the use of acrolein 28 resulted in an unidentified mixture of polymers (Table 2, entry 1). On the other hand, allylamine 30 furnished an imidazoline bearing a terminal alkene substituent 29 suitable for, e.g., olefin metathesis or rhodium-catalysed ring closure (entry 2).3 The ease with which unprotected alcohols in both the amine and the aldehyde component can be accommodated is illustrated by entries 3–5. Because of insolubility of the imine derived from amine 37 and aldehyde 35 in DCM, the synthesis of 2-imidazoline 38 was performed in methanol. After flash column chromatography, imidazoline 38 was still contaminated with amine 37. Crystallisation was necessary to obtain the pure product.

Many studies are dedicated to the promising abilities of multivalent ligands and inhibitors

for the manipulation of polyvalent interactions between biological entities.4 It has been


37

established that, in comparison with their monomeric counterparts, dimeric molecules often show higher biological activity. Therefore, we decided to investigate the potential of our MCR to access products containing multiple 2-imidazoline units connected by various tethers. Such bis-imidazolines would be valuable precursors for bidentate NHC ligands for transition metal catalysis as well. In Scheme 2 and Scheme 3, the synthesis of two different bis-imidazolines is illustrated.

Table 2. 2-Imidazolines from functionalised amines and aldehydes and 4 entry amine aldehyde product yielda

1 NH2

10

O28

N

N

29

0%

2 NH230

O8

N

N

31

91%

3 NH232

OH

pCH2O33

N

N

34

OH

83%

4

NH212

OMe

O35

OH

N

N

36

PMB

HO

68%

5b NH2

37

HO

O35

OH

N

N

38

HOOH

38%c

a Isolated yields are reported. b Reaction was performed in methanol. c Yield after flash column chromatography and crystallisation.

Chapter 3

38

Reaction of hexane-1,6-diamine 39 with isobutyraldehyde 8 (2 equiv) and 9-isocyanofluorene 4 (2 equiv) efficiently provides hexane-tethered bis-imidazoline 40 (Scheme 2). With both 1H and 13C NMR measurements, no distinction between the two possible diastereomers could be made.

Scheme 2

N N

NNH2N NH2

Na2SO4

DCM67%

ONC

+ +

39 8 4 40

Reaction of isophtalaldehyde 41 with isopropylamine 10 (2 equiv) and 4 (2 equiv) gave bis-imidazoline 42 containing a somewhat more rigid tether (Scheme 3). Again, the diastereomeric ratio could not be determined from the NMR data.

Scheme 3

NN NNOONH2

Na2SO4

DCM55%NC

+ +

10 41 4 42

3.3 MCRs with p-Nitrobenzyl Isocyanide and Allyl Isocyanide

Because further variation of the isocyanide component in the multicomponent synthesis of 2-imidazolines would significantly increase the versatility of the reaction, additional isocyanides with acidic α-protons were considered as well. In order to synthesise 4-monosubstituted 2-imidazolines 43, we explored the use of isocyanides with the general structure 44 (Scheme 4).

Scheme 4

N

N

EWG

R2R1

NCEWG

43 44

p-Nitrobenzyl isocyanide 44a was envisioned as an isocyanide of type 44 that still contains a rather acidic methylene unit. It was synthesised from the corresponding amine 45, which was prepared according to a literature procedure,5 in two steps (overall yield 98%, Scheme 5).


39

Scheme 5a

NH2

NO2

NH

NO2

NC

NO2

a

100%

b

98%

O

45 46 44a a Reagents and conditions: (a) acetic formic anhydride, DCM, 0 ºC to rt, 1 h; (b) Et3N, POCl3, THF, −78 ºC to 0 ºC, 1 h.

The first attempt to allow 44a to react with the in situ generated imine of isopropylamine 10 and isobutyraldehyde 8 did not result in the formation of the desired product 47 (Table 3, entry 1). Only imine and isocyanide 44a could be isolated. Also performing the reaction at a higher temperature was unsuccessful (entry 2). Instead of using even higher temperatures to obtain the 2-imidazoline 47, another method was conceived. Several studies have been conducted on the increased acidity of α-protons of isocyanides coordinated to metals.6 Transition metal catalysed cycloadditions of various isocyanoacetates,7 benzyl isocyanide8 and allyl isocyanide9 to a range of electron-poor olefins or aldehydes have been reported. The cycloaddition to imines however required C=N bond activation by the introduction of a sulfonyl group on the imine nitrogen.10 In 1999, Grigg et al. described the efficient silver(I) acetate catalysed cycloaddition of methyl isocyanoacetate to Michael acceptors.11 We envisioned silver(I) acetate as a suitable Lewis acid to activate p-nitrobenzyl isocyanide 44a. Indeed, one-pot reaction of 44a with 10 and 8 in the presence of only 2 mol% silver(I) acetate provided 2-imidazoline trans-47 in 39% yield as a single diastereomer (Table 3, entry 3).

Table 3. Synthesis of 4-momosubstituted 2-imidazoline 45

NC

NO2

44a

ONH2

10 8

+Na2SO4

DCM N

N

O2N

N

N

O2N

+

trans-47 cis-47

+

entry T, ºC catalyst yield,a %

1 20 none 0b

2 60c none 0b 3 20 AgOAcd 39 (trans)e,f

a Isolated yields are reported. b Only imine and isocyanide 44a were recovered. c Heating was performed using a single mode microwave oven (CEM). d 2 mol % of AgOAc was used. e Relative stereochemistry was determined from the 1H NMR coupling constants of H-4 and H-5. f Also the corresponding imidazole 48 was isolated in 27% yield.

Chapter 3

40

Besides trans-47, another product was isolated in 27% yield after flash column chromatography.12 This product was identified as imidazole 48 (Scheme 5). Apparently, some of the initially formed imidazoline 47 had been oxidised during the reaction or during workup/purification.13 Because complete diastereoselectivity had never been observed before in our MCR, we reasoned that 48 should be formed from cis-47. To test this hypothesis, and to examine the factors causing the oxidation, both the MCR and subsequent workup were performed under exclusion of oxygen. Indeed, in the crude product a mixture of trans-47 and cis-47 could be observed in a ratio of 58:42 according to 1H NMR. When this crude mixture was subjected to air, cis-47 was rapidly oxidised to 48, even in the absence of light. Also trans-47 is not infinitely air-stable. After storing a purified sample for half a year under air, it contained about 75% of the oxidised product 48. In conclusion, 48 is a product of the air oxidation of cis-47 (fast) and/or trans-47 (very slow) (Scheme 6). For this oxidation, neither silver(I) catalyst nor light is needed.

Scheme 6

The proposed mechanism for the silver(I) catalysed MCR with p-nitrobenzyl isocyanide 44a is depicted in Scheme 7. We propose that the activated isocyanide 32 is deprotonated by either the acetate anion or a trace of amine present in the reaction mixture (acting as base B after in situ imine formation). Then, the imine 50 is attacked by the deprotonated complex 51 to give aldol adduct 52.

Scheme 7


41

Ring closure of the secondary amine followed by exchange of the silver(I) cation for a

proton would provide the 2-imidazoline 43a. The formation of 52 from 50 and 51 may proceed via either a concerted cycloaddition or a stepwise mechanism. An alternative pathway would involve the aldol-type addition to an iminium ion intermediate.

Chart 1

Variation of the amine and aldehyde substituents gave two more p-nitrophenyl

substituted imidazolines 54 and 56 in reasonable to good yields (Chart 1). According to NOESY measurements, for 2-imidazoline 54, the cis-diastereomer was formed in excess. In the crude product of 56, both the trans- and cis-diastereomers could be detected in a 62:38 ratio. However, after flash column chromatography only trans-56 and the corresponding imidazole 57 (11%) were isolated. Both diastereomers of 54 appeared to be much more air-stable. Nevertheless, after storing the mixture for months under air, both diastereomers were oxidised to the imidazole 55.

Scheme 8

The air oxidation of 2-imidazolines could proceed via a radical stabilised by the p-nitrophenyl group (Scheme 8). Because of this stabilisation, oxidation of both trans-43a and cis-43a should proceed via the same radical intermediates 58. For the cis-diastereomers, the two substituents at C–4 and C–5 move away from each other during this radical formation (this reduces the steric repulsion), whereas for the trans-diastereomers, these groups move towards each other (this increases the steric repulsion). Formation of 58 should be faster from the cis-diastereomers than from the trans-diastereomers. This is supported by density functional theory (DFT)14 calculations that

Chapter 3

42

show the trans-imidazolines to be more stable than their cis-counterparts by 2–5 kcal mol−1 (Table 4).

Table 4. Calculated energy differences between cis- and trans-imidazolines entry compound ∆E(cis)−(trans) (kcal mol−1)a

1 47 4.0 2 54 2.0 3 56 4.7

a BP86/TZP

Encouraged by the good results in the silver(I) catalysed reactions of 44a, allyl

isocyanide 44b was tested in order to synthesise more 2-imidazolines of type 43. Combination of p-methoxybenzylamine 12, p-anisaldehyde 16 and 44b without catalyst did not result in any imidazoline formation (Scheme 9). Addition of silver(I) acetate to the reaction mixture did not promote the cycloaddition. In both cases, only the imine derived from 12 and 16 was isolated after evaporation of the solvent and unreacted 44b.15 Apparently, the reactivity of activated allyl isocyanide towards imines is considerably lower compared to that of 44a.16

Scheme 9a

O

OMe

NH2

12

OMe

16

NCN

N

MeO OMe

44b 59

+ +

a or b

X

a Reagents and conditions: (a) Na2SO4, DCM, rt, 18 h; (b) Na2SO4, AgOAc (2 mol %), DCM, rt, 18 h.

3.4 Rationalisation of Difference in Reactivity Using DFT Calculations

To rationalise the differences in reactivity of the various isocyanides in our MCR, DFT (BP86/TZ2P) calculations proved helpful. The mechanism for the aldol-type addition probably involves deprotonation of the isocyanide followed by attack of the anion to the (protonated) imine (Scheme 7). Three aspects are important for understanding the reactivity, which are the proton affinity (PA) of the isocyanide (which correlates to the acidity), the orbital energy of the highest occupied molecular orbital (HOMO) of its carbanion, and the contribution of carbanion orbitals in the HOMO. The PA of a molecule BH is defined as the system’s enthalpy change for the reaction BH → B– + H+. Hence, a smaller PA corresponds to a larger concentration of the B– anion. The difference in energy between the HOMO of the attacking deprotonated complex and the lowest unoccupied orbital (LUMO) of the imine (or the iminium ion) determines the interaction between the


43

two. Thus, the reactivity is governed by the [B-], the HOMO-LUMO gap, and the contribution of carbanion orbitals in the HOMO.

The computational setup for calculating PAs was validated against a series of organic and

inorganic bases, for which experimental data are available.17 It was shown that DFT gives both qualitatively and quantitatively good results for proton affinities.18 Solvent effects (DCM) are properly taken into account by the COSMO model.19 DFT calculations were performed for five different isocyanides: 9-isocyanofluorene 4, methyl 2-isocyano-2-phenylacetate 60, methyl isocyanoacetate 61, p-nitrobenzyl isocyanide 44a and allyl isocyanide 44b (Table 5).

Table 5. Computed proton affinities (kcal mol−1) of isocyanides and orbital energies of the HOMOs (eV) and contributions of pZ-orbitals in HOMOs (%) of their anionsa,b

NC

44b

NC

Ph

NCMeO2C NCMeO2C

NO2

NC

44a61604 entry isocyanide Ag+ coordinated PA (kcal mol−1) εHOMO (eV) % pz(Canion)

1 4 no 180.3 −3.87 31.5 2 60 no 181.4 −3.63 27.4 3 61 no 190.3 −3.91 47.6 4 44a no 181.9 −4.01 27.9 5 44a yes 170.2 −4.63 27.3 6 44b no 200.8 −3.01 36.9 7 44b yes 179.5 −4.31 26.1 a BP86/TZ2P. b In all calculations, DCM was taken as the solvent.

The two isocyanides that display the highest reactivity in our MCR, 4 and 60 (entries 1

and 2), have similar values for the PA (ca. 181 kcal mol−1), HOMO orbital energy (ca. –3.7 eV) and contribution of carbanion (pz) orbital in the HOMO (ca. 30 %). These values can be taken as reference values for the reactivity of isocyanides in our MCR. Methyl isocyanoacetate 61 (entry 3) has a larger contribution of carbanion orbitals in the HOMO, in fact the largest of all isocyanides we studied, and a HOMO orbital energy that is comparable to that of 4 (entry 1). However, its proton affinity is almost 10 kcal mol−1 larger than that of 4 and 60, which would result in a lower carbanion concentration and hence a lower reactivity. This is consistent with our previously reported experiments (Chapter 2). Although its PA and contribution of the carbanion orbital in the HOMO are similar to those of 60 (entry 2), p-nitrobenzyl isocyanide 44a (entry 4) does not react with imines in the absence of silver(I). Its non-reactivity is ascribed to its HOMO being 0.4 eV lower in

Chapter 3

44

energy than that of 60. The activation by silver(I) has mainly an effect on the PA of 44a, which is reduced by almost 12 kcal mol−1 (entry 5). Consequently, the concentration of carbanion increases significantly, which apparently compensates for the still rather poor εHOMO and causes the reaction to proceed after activation. Based on the HOMO orbital energy and the contribution of the carbanion pz-orbital in it, allyl isocyanide 44b should be able to react with imines, were it not for its very high PA, which is, in fact, the highest of the series. Preliminary results suggest that the PA of allyl groups may even be underestimated by our computational setup by up to 5 kcal mol−1. This makes it unlikely that any carbanions are present (entry 6). After activation by silver(I), the PA becomes comparable to that of 4 or 60, which should be sufficient for reaction, but both the HOMO orbital energy and the contribution of the carbanion pz-orbital in the HOMO decrease dramatically, by 1.3 eV and from 37% to 26%, respectively (entry 7). As a result, the carbanions will not be reactive towards imines. Furthermore, it was found that, for the anion of 44b, not the isocyano group but the allyl group is the energetically favoured coordination site for silver(I) (a difference of ca. 5 kcal mol−1, see Computational Details section). This thermodynamically more stable complex has a HOMO energy of –5.10 eV and a contribution of the carbanion pz-orbital of only 22.9 %. Therefore, nucleophilic attack would be even more hampered.

3.5 Application of Ketones

Instead of aldehydes, also ketones could be imagined as the oxo-components in the multicomponent synthesis of 2-imidazolines. However, both steric and electronic effects might decrease the reactivity of the in situ formed ketimines. The first attempts to apply cyclohexanone 62 in the MCR gave disappointing results (Table 6). With either 9-isocyanofluorene 4 or p-nitrobenzyl isocyanide 44a, no 2-imidazoline was formed at all (entries 1 and 3, method A). Employing methyl 2-isocyano-2-phenylacetate 60 as the isocyanide component gave the expected 5-disubstituted product, albeit in only 7% yield (entry 2, method A). Addition of a catalytic amount of silver(I) acetate appeared to be sufficient to activate the isocyanides to such an extent that reaction with the less electrophilic ketimines (as compared to the similar aldimines) is accelerated, which resulted in significantly increased yields (entries 1–3, method B). The somewhat low yield for 44 is probably the result of steric factors. This is supported by experiments that combine acetone 66, benzylamine 71 and isocyanides (4, 60, and 44a) in the silver(I) catalysed MCR, which furnished 2-imidazolines 67–69 (entries 4–6, method B). Even with 9-isocyanofluorene 4 a good yield was obtained now.

When 3-(chloromethyl)cyclobutanone 7020 was applied, no additional catalyst was

needed to perform the MCR (Scheme 10). Reaction of 70, benzylamine 71 and 9-isocyanofluorene 4 provided 2-imidazolines 72a and 72b, which contain a chloromethyl


45

unit suitable for further derivatisation, as a mixture of isomers. The identity of the trans-isomer 72a was established by NOE measurements. Also isocyanoacetate 60 gave good results in a reaction with 70 and 71 (Scheme 11).21 Again, NOE measurements were used for the identification of the trans-isomer 73a. The relatively high reactivity of imines derived from cyclobutanone 70 compared to the other ketimines can be accounted for by the release of ring strain, going from an sp2 ring carbon to an sp3 ring carbon.

Table 6. MCRs with ketones as the oxo-componenta

entry ketone isocyanide product yield Ab yield Bc

1 O

62

NC

4

N

N

Ph

63

0%d 20%

2 O

62

Ph

NCMeO2C

60

N

N

Ph

MeO2CPh

64

7% 55%

3 O

62

NO2

NC44a

N

N

Ph

O2N 65

0%d 77%

4 O

66

NC

4

N

N

Ph

67

nd 72%

5 O

66

Ph

NCMeO2C

60

N

N

Ph

MeO2CPh

68

nd 62%

6 O

66

NO2

NC44a

N

N

Ph

O2N 69

nd 67%

a In all reactions, benzylamine 71 was used as the amine input. b Method A: Na2SO4, DCM, 18 h, rt. Isolated yields are reported. c Method B: AgOAc (2 mol %), Na2SO4, DCM, 18 h, rt. Isolated yields are reported. d Only imine and isocyanide were isolated.

Chapter 3

46

Scheme 10

N

N

Ph

72b, 25%

H

N

N

Ph

72a, 38%

HCl Cl

O

Cl

NH2

Ph

NC

470 71

Na2SO4

DCM+ + +

NOE

Scheme 11

N

N

Ph

MeO2CPh

73a, 30%

H

N

N

Ph

MeO2CPh

73b, 24%

HCl Cl

Ph

NCMeO2C

60

Na2SO4

DCM++

O

Cl

NH2

Ph

70 71

+

NOE

3.6 Application of Chiral Amines and Aldehydes

For the synthesis of enantiopure molecules, chemists depend on the availability of chiral starting materials, reagents, auxiliaries, or catalysts. In this regard, the general importance of chiral amines is well recognised and α-phenylethylamine (α-PEA) is known as a simple, yet powerful chiral adjuvant. Both enantiomers are commercially available and relatively cheap. Therefore, their recovery may not be critical even after use on a large scale. Furthermore, the chiral group can be removed from the amine easily using reductive conditions. These aspects of α-PEA have made it very popular for a wide range of imine-based diastereoselective reactions.22 Imines resulting from the condensation of α-PEA and aldehydes are conformationally locked in the ground state 74b (the C–H bond eclipsing the double bond), since conformations 74a and 74c are substantially destabilised by allylic 1,3-strain (Scheme 12).23 Thus, the diastereotopic faces at the prochiral imine C=N will be differentiated by the difference in size of the substituents at the stereogenic centre (H vs Me vs Ph), since factors that influence reactant conformational energies will also influence transition state conformational energies.

Scheme 12

NR1

R2

HPh

Me

NR1

R2

MePhH

NR1

R2

PhHMe

74a 74b 74c


47

Combination of (R)-α-phenylethylamine 75 with isocyanide 4 and either isobutyraldehyde 8 or p-anisaldehyde 16 did afford the expected 2-imidazolines in reasonable to very high yields (Table 7, entries 1 and 2), but the diastereoselectivities were poor. In contrast with earlier observations (Chapter 2, Table 2), in this case the solvent does influence the diastereoselectivity of the MCR. In addition, some experiments were performed with (−)-myrtenal 78 as chiral aldehyde (entries 3 and 4). Again, high yields were obtained and, when methanol was used as the solvent, rather good diastereoselectivities were achieved.

Table 7. Application of chiral amines and aldehydesa entry amine aldehyde product yield Ab (dr)c yield Bd (dr)c

1 NH2

Ph

75

O8

N

N

Ph

76

97% (63:37) 89% (77:23)

2 NH2

Ph

75

O16

OMe

N

N

Ph

77

MeO

77% (56:44) 53% (48:52)

3 NH2

10

O78

N

N

79

81% (37:63) 86% (83:17)

4

NH227

OMe

O78

N

NPMB

80

75% (55:45) 67% (95:5)

a In all reactions, 9-isocyanofluorene 4 was used as the isocyanide input. b Method A: Na2SO4, DCM, 18 h, rt. d

Isolated yields and diastereomeric ratios are reported. d Method B: Na2SO4, MeOH, 18 h, rt.

Since the application of α-PEA did not result in high diatereoselectivities and the use of

chiral amines or aldehydes causes a substantial limitation of the exploratory power of this MCR, efforts towards diastereoselective reactions were postponed at this point. In future investigations, the influence of different solvents on the diastereoselectivity of the

Chapter 3

48

multicomponent synthesis of 2-imidazolines should be explored more thoroughly. Furthermore, the enantioselective multicomponent synthesis of 2-imidazolines using transition metal catalysts combined with chiral ligands is currently under investigation. Application of this method should ideally preserve the exploratory power of the MCR.

3.7 Conclusions

The scope of the multicomponent synthesis of 2H-2-imidazolines from isocyanides bearing acidic α-protons and in situ generated imines has been studied extensively. Three different isocyanides were used in combination with aldehydes and amines containing a variety of simple and functionalised side chains. The most important limitations are the steric bulk of the imine substituents and the reactivity of the isocyanide. Both the ease with which the isocyanide is deprotonated and the reactivity of the anion are important. Silver(I) catalysis appeared to be an excellent method to promote both difficult aldol-type additions to ketimines and reactions with p-nitrobenzyl isocyanide 44a. The resulting p-nitrophenyl substituted 2-imidazolines are relatively unstable to air. Both diastereomers are oxidised under air exposure (although at different rates) to the corresponding imidazoles. This MCR/oxidation procedure could be developed towards a useful and flexible imidazole synthesis complementary to Sisko’s methodology.24 For the application of allyl isocyanide 44b in the MCR, probably stronger activators for either the isocyanide or the imine are required. Finally, when chiral amines or aldehydes are used, the solvent has substantial influence on the diastereoselectivity of the MCR.


Dr. Marek Smoluch (Vrije Universiteit Amsterdam) and Dr. Maarten Posthumus (Agricultural University Wageningen) are gratefully acknowledged for conducting (HR)MS measurements. Prof. Dr. Christian V. Stevens (Ghent University) is kindly acknowledged for supplying 3-(chloromethyl)cyclobutanone 70. Dr. Marcel Swart and Dr. F. Matthias Bickelhaupt thank The Netherlands organisation for Scientific Research (NWO-CW) for financial support.

3.9 Computational Details

DFT (BP86) calculations were performed using the Amsterdam Density Functional (ADF) program.25 The MOs were expanded in large uncontracted sets of Slater-type orbitals (STOs),26 which are of triple-ζ quality, augmented by one (TZP: 3d on C, N, O; 2p on H) or two sets of polarisation functions (TZ2P: 3d and 4f on C, N, O; 2p and 3d on H; 5p and 4f on Ag); the 1s core shell of carbon, nitrogen, oxygen and the 1s–3d core shells of silver were treated by the frozen core (FC) approximation.25b An auxiliary set of s, p, d, f, and g STOs was used to fit the molecular density and to represent the Coulomb and


49

exchange potentials accurately in each SCF cycle. For the silver containing systems, (scalar) relativistic effects were taken into account using the zeroth-order regular approximation (ZORA).25b,27 Energies and gradients were calculated using the local density approximation (LDA; Slater exchange and VWN correlation)28 with non-local corrections due to Becke29 (exchange) and Perdew30 (correlation) added self-consistently. This xc-functional is one of the three best DFT functionals for the accuracy of geometries,31 with an estimated unsigned error of 0.009 Å in combination with the TZ2P basis set. Geometries were optimised using analytical gradient techniques until the maximum gradient component was less than 1.0 × 10−4 atomic units. Vibrational frequencies were obtained through numerical differentiation of the analytical gradients.25b

The proton affinity (PA) of a molecule is defined as the system’s enthalpy change for the

reaction BH → B– + H+.17 The enthalpy correction to the electronic energy of the systems was calculated from the vibrational frequencies using the usual thermochemistry relations32 Solvent effects representing dichloromethane were taken into account for the isocyanides using the Conductor like Screening Model (COSMO),19a as implemented in the ADF program.19b Scaled MM3 atomic radii33 (scaling factor 0.8333) have been used as these are available for (almost) all elements. We used values of 1.350 Å (H), 1.700 (C), 1.608 (N), 1.517 (O), and 2.025 Å (Ag). With these radii, the difference between computed and experimental hydration energies is <3 kcal mol−1 for chloride anion (75.0 kcal mol−1 theor. vs 76.0 exp.), tetramethylammonium cation (53.5 theor. vs 50.4 exp.) and tert-butyl cation (55.8 theor.).34 A solvent-excluding surface was used with an effective radius for water of 1.9 Å, derived from the macroscopic density and molecular mass, and a dielectric constant of 78.4. For dichloromethane, a solvent radius of 3.55 Å and a dielectric constant of 8.9 has been used.

NO2

NC

NC Ag++Ag

+Ag

Ag+

+Ag Ag+A

B

C

A

B

C

Figure 2. Coordination of Ag+ cation to the anion of isocyanides 42a (left) and 42b (right)

We have also considered alternative coordination sites for silver available in compounds 44a and 44b (Figure 2), which may also contribute to the observed trend in relative reactivities. Instead of coordinating at isocyanide (position C), in the anionic species of 44a it can also coordinate to the carbanion (position A) or to the nitro group (position B). However, both are less favourable than coordination at the isocyanide, by 6.8 (carbanion) or 10.3 kcal mol−1 (nitro). For the anionic species of 44b, coordination sites are present at positions A, B and C. Coordination at A, which would hamper nucleophilic attack, is less

Chapter 3

50

favourable than coordination at position C by only 1.6 kcal mol−1. Coordination at B is even more favourable than coordination at C by 5.3 kcal mol−1. For the neutral species, the Ag+@B complex is less favourable than the Ag+@C complex by 17.1 kcal mol−1. Therefore, in the protonated form the silver(I) cation prefers to be coordinated at position C of 44b, while in the deprotonated form, it prefers the B coordination. This influences the reactivity of 44b in a negative manner, as the Ag+@B complex has a HOMO orbital energy that is 0.7 eV below the Ag+@C complex, which hinders reactivity.

Coordinates and energies of all optimised structures can be found in the Supporting

Information of: J. Org. Chem. 2005, 70, 3542–3553. This file is available free of charge via the Internet at http://pubs.acs.org.


General Information: All reactions were carried out under an inert atmosphere of dry nitrogen. Standard syringe techniques were applied for transfer of air sensitive reagents and dry solvents. Melting points were measured using a Stuart Scientific SMP3 melting point apparatus and are uncorrected. Infrared (IR) spectra were obtained from CHCl3 films on NaCl tablets (unless noted otherwise), using a Matteson Instuments 6030 Galaxy Series FT-IR spectrophotometer and wavelengths (ν) are reported in cm−1. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 (400.13 MHz and 100.61 MHz respectively) or a Bruker Avance 250 (250.13 MHz and 62.90 MHz respectively) with chemical shifts (δ) reported in ppm downfield from tetramethylsilane. MS and HRMS spectra data were recorded on a Finnigan Mat 900 spectrometer or in the Laboratory of Organic Chemistry of the Wageningen University (NL) on a Finnigan MAT95 spectrometer. Chromatographic purification refers to flash chromatography using the indicated solvent (mixture) and Baker 7024-02 silica gel (40μ, 60 Å). Thin Layer Chromatography was performed using silica plates from Merck (Kieselgel 60 F254 on aluminium with fluorescence indicator. Compounds on TLC were visualised by UV-detection. THF was dried and distilled from sodium benzophenone ketyl prior to use. DCM was dried and distilled from CaH2 prior to use. Petroleum ether (PE 40–65) was distilled prior to use. Triethylamine and isopropylamine were dried and distilled from KOH pellets. Furfural, isobutyraldehyde and benzaldehyde were distilled and stored over MS 4Å under a dry nitrogen atmosphere. Phosphoryl chloride was distilled from P2O5 and stored under a dry nitrogen atmosphere. Acetic formic anhydride was prepared by stirring 1 equiv. of acetic anhydride and 1.2 equiv. of formic acid for 2 h at 55°C used as such. Other commercially available reagents were used as purchased.

9-formylamino-9H-fluorene 6 To a stirred solution of 9-amino-9H-fluorene 5 (3.33 g, 18.4 mmol) in 50 mL DCM at 0°C, acetic formic anhydride (5 mL) was added drop wise. Stirring was continued for 1 h at rt. Evaporation of the solvent and acids at reduced pressure yielded the N-formamide 6 (3.77 g, 98%) as a white solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 8.51 (s, 1H),

7.78–7.23 (m, 8H), 6.39 (d, J = 12.2 Hz, 1H), 5.75 (br s, 1H).

9-isocyano-9H-fluorene 4 To a stirred solution of 6 (3.94 g, 18.9 mmol) in 20 mL dry THF at −78°C, Et3N was added (13.2 mL, 94.5 mmol). Then, POCl3 (2.1 mL, 22.7 mmol) in 60 mL dry THF was added drop wise. The reaction mixture was allowed to warm to 0°C and stirred for 1 h.

Then, the mixture was poured into 40 mL of ice cold water. The mixture was extracted with Et2O (3 × 30 mL). The combined organic layers were extracted with brine (20 mL), dried with Na2SO4 and concentrated in vacuo to afford 4 (4.0 g, 61%) as dark red solid. Mp 87.1–91.4 °C; 1H NMR (250 MHz, CDCl3): δ (ppm) 7.76–7.69 (m, 4H), 7.55–7.38 (m, 4H), 5.66 (s, 1H); 13C NMR (63 MHz): δ (ppm) 140.1 (C), 139.5 (C), 129.8 (CH), 128.3 (CH),

NC

HN

O


51

124.8 (CH), 120.3 (CH), 56.7 (CH, t, JC,N = 6.8 Hz)), The isocyanide carbon could not be observed; IR (KBr): 2141 (s), 1715 (m), 1451 (s). General Procedure I for the Synthesis of 2-Imidazolines: Reactions were carried out at a concentration of 1 M of amine, 1 M of aldehyde (or ketone) and 0.5 M of isocyanide in dry DCM, unless noted otherwise. Na2SO4 and the aldehyde (or ketone) were added, at rt, to a stirred solution of the amine. After the mixture was stirred for 2 h, the isocyanide was added and the reaction mixture was stirred at rt for an additional 18 h. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (PE:EtOAc:Et3N = 2:1:0.01, gradient, unless stated otherwise).

2-Imidazoline 9. According to General Procedure I, reaction between benzhydrylamine 7 (732 mg, 4.0 mmol), isobutyraldehyde 8 (288 mg, 4.0 mmol) and 4 (315 mg, 1.6 mmol), followed by column chromatography (PE:EtOAc:Et3N = 10:1:0.01, gradient), afforded 9 (137 mg, 20%) as a colourless oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.56–6.76 (m, 19H), 5.64 (s, 1H), 3.58 (d, J = 7.0 Hz, 1H), 1.95 (m, 1H), 0.73 (d, J = 6.9 Hz, 3H), 0.38 (d, J = 6.9 Hz, 3H); 13C NMR (63

MHz): δ (ppm) 158.1 (CH), 150.9 (C), 145.8 (C), 140.7 (C), 140.4 (C), 140.2 (C), 137.6 (C), 129.1 (2×CH), 129.0 (2×CH), 128.7 (2×CH), 128.4 (2×CH), 128.3 (CH), 128.2 (CH, 128.2 (CH), 127.8 (CH), 127.7 (CH), 126.8 (CH), 126.8 (CH), 124.4 (CH), 119.7 (CH), 119.5 (CH), 83.0 (C), 72.8 (CH), 64.9 (CH), 28.8 (CH), 19.81 (CH3), 19.79 (CH3); IR (neat): 3061 (s), 3030 (s), 2963 (s), 2930 (s), 2872 (s), 1599 (s), 1493 (s), 1448 (s), 1163 (s).

2-Imidazoline 11. According to General Procedure I, reaction between isopropylamine 10 (177 mg, 3.0 mmol), isobutyraldehyde 8 (216 mg, 3.0 mmol) and 4 (216 mg, 1.13 mmol), followed by column chromatography, afforded 11 (285 mg, 84%) as a colourless oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.58–7.08 (m, 9H), 3.62 (d, J = 7.3 Hz, 1H), 3.39 (m, 1H), 1.79 (m, 1H), 1.40 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H), 0.67 (d, J = 6.9 Hz, 3H), 0.29 (d, J = 6.8 Hz, 3H); 13C

NMR (101 MHz): δ (ppm) 156.8 (CH), 151.1 (C), 145.7 (C), 140.6 (C), 140.5 (C), 128.2 (2×CH), 127.7 (CH), 126.8 (CH), 126.7 (CH), 124.2 (CH), 119.7 (CH), 119.6 (CH), 82.6 (C), 72.8 (CH), 29.2 (CH), 22.2 (CH), 20.0 (2×CH3), 19.6 (CH3), 19.5 (CH3); IR (neat): 2965 (s), 2930 (s), 1674 (s), 1605 (s), 1449 (s), 1238 (s).

2-Imidazoline 13. According to General Procedure I, reaction between p-methoxybenzylamine 12 (274 mg, 2.0 mmol), isobutyraldehyde 8 (144 mg, 2.0 mmol) and 4 (192 mg, 1.0 mmol), followed by column chromatography, afforded 13 (348 mg, 91%) as a brown oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.69–7.00 (m, 13H), 4.64 (d, J = 14.9 Hz, 1H), 4.26 (d, J = 14.9 Hz, 1H), 3.88 (s, 3H), 3.55 (d, J = 8.2 Hz, 1H), 2.03 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H), 0.29 (d, J = 6.7 Hz,

3H); 13C NMR (63 MHz): δ (ppm) 160.9 (CH), 159.2 (C), 150.9 (C), 145.8 (C), 140.5 (C), 140.2 (C), 129.7 (2×CH), 128.1 (CH), 128.0 (CH), 127.9 (C), 127.6 (CH), 126.8 (CH), 126.3 (CH), 126.0 (CH), 124.2 (CH), 119.6 (CH), 119.4 (CH), 114.1 (2×CH), 83.2 (C), 71.9 (CH), 55.2 (CH3), 52.6 (CH2), 29.7 (CH), 20.7 (CH3), 20.0 (CH3); IR (neat): 1609 (s), 1512 (s), 1449 (m), 1218(s).

2-Imidazoline 15. According to General Procedure I, reaction between tryptamine 14 (320 mg, 2.0 mmol), isobutyraldehyde 8 (144 mg, 2.0 mmol) and 4 (288 mg, 1.56 mmol), followed by column chromatography, afforded 15 (428 mg, 67%) as a yellow powder. Mp 234.0–234.5 oC (decomposes); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.50 (br s, 1H), 7.57–7.53 (m, 3H), 7.35–7.06 (m, 10H), 6.92 (d, J = 2.0 Hz, 1H), 3.75 (d, J = 7.5 Hz,

1H), 3.57 (m, 2H), 3.12 (m, 2H), 1.88 (m, 1H), 0.81 (d, J = 6.8 Hz, 3H), 0.28 (d, J = 5.8 Hz, 3H); 13C NMR (101 MHz): δ (ppm) 160.2 (CH), 152.1 (C), 145.8 (C), 140.6 (C), 140.5 (C), 136.4 (C), 128.3 (CH), 128.2 (CH), 127.7 (CH), 127.1 (C), 126.9 (CH), 126.5 (CH), 124.3 (CH), 122.4 (CH), 122.1 (CH), 119.8 (CH), 119.7 (CH), 119.5 (CH), 118.4 (CH), 113.8 (C), 111.5 (CH), 83.1 (C), 73.5 (CH), 48.4 (CH2), 29.6 (CH), 23.7 (CH2), 20.4 (CH3), 20.1 (CH3); IR (KBr): 3420 (s/br), 1588 (s), 1449 (m), 735 (s); MS (EI, 70 eV) m/z (%) = 405 (53) [M]+, 362 (1),

N

N

PhPh

N

N

N

NPMB

N

NNH

Chapter 3

52

275 (4), 263 (6), 240 (33), 215 (65), 206 (15), 144 (100), 130 (23); HRMS (EI, 70 eV) calculated for C28H27N3 (M+) 405.2205, found 405.2207.

2-Imidazoline 17. According to General Procedure I, reaction between isopropylamine 10 (118 mg, 2.0 mmol), p-anisaldehyde 16 (272 mg, 2.0 mmol) and 4 (192 mg, 1.0 mmol), followed by column chromatography, afforded 17 (262 mg, 70%) as a yellow oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.66 (s, 1H), 7.51–7.47 (m, 2H), 7.34–7.27 (m, 3H), 7.04–6.88 (m, 3H), 6.63 (d, J = 8.6 Hz, 2H), 6.47 (d, J = 8.8 Hz, 2H), 4.95 (s, 1H), 3.56 (s, 3H), 3.28 (m, 1H), 1.46 (d, J = 6.9 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H); 13C NMR (63 MHz): δ (ppm) 158.5 (C), 156.4 (CH), 150.1

(C), 145.1 (C), 140.8 (C), 139.1 (C), 128.3 (CH), 128.0 (C), 127.8 (2×CH), 127.7 (CH), 126.6 (CH), 126.0 (CH), 123.9 (CH), 119.4 (CH), 119.2 (CH), 113.1 (2×CH), 84.1 (C), 72.2 (CH), 55.0 (CH3), 46.5 (CH), 22.1 (CH3), 20.2 (CH3); IR (neat): 1592 (s), 1512 (s), 1246 (s).

2-Imidazoline 18. According to General Procedure I, reaction between p-methoxybenzylamine 12 (548 mg, 4.0 mmol), p-anisaldehyde 16 (544 mg, 4.0 mmol) and 4 (382 mg, 2.0 mmol), followed by column chromatography, afforded 18 (714 mg, 80%) as a white solid. Mp 154.6–156.7 oC; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.69 (s, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.36–7.33 (m, 1H), 7.30–7.28 (m, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.16–7.10 (m, 2H), 7.02 (m, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 8.5 Hz, 2H),

4.78 (s, 1H), 4.59 (d, J = 14.4 Hz, 1H), 4.04 (d, J = 14.4 Hz, 1H), 3.87 (s, 3H), 3.68 (s, 3H); 13C NMR (101 MHz): δ (ppm) 159.4 (C), 159.2 (CH), 158.7 (C), 149.7 (C), 145.1 (C), 140.9 (C), 139.8 (C), 129.9 (2×CH), 128.3 (CH), 127.9 (2×CH), 127.9 (CH), 127.7 (CH), 127.6 (C), 126.9 (C), 126.7 (CH), 126.1 (CH), 124.1 (CH), 119.4 (CH), 119.3 (CH), 114.2 (2×CH), 113.3 (2×CH), 84.6 (C), 72.0 (CH), 55.3 (CH3), 55.0 (CH3), 49.8 (CH2); IR (neat): 1609 (s), 1593 (s), 1512 (s), 1248 (s).

2-Imidazoline 20. According to General Procedure I, reaction between p-methoxybenzylamine 12 (548 mg, 4.0 mmol), o-anisaldehyde 19 (544 mg, 4.0 mmol) and 4 (382 mg, 2.0 mmol), followed by column chromatography, afforded 20 (714 mg, 80%) as a yellow oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.63 (s, 1H), 7.59 (d, J = 7.0 Hz, 1H), 7.51–7.41 (m, 2H), 7.32–7.23 (m, 4H), 7.13–7.06 (m, 3H), 7.00–6.93 M, 3H), 6.89–6.82 (m, 1H), 6.76–6.69 (m, 1H), 6.40 (d, J = 8.0 Hz, 1H), 5.17 (s, 1H), 4.69 (d, J = 14.5 Hz, 1H), 4.13 (d, J = 14.5 Hz, 1H), 3.88 (s, 3H), 2.88

(br s, 3H); 13C NMR (101 MHz): δ (ppm) 159.4 (C), 157.9 (CH), 157.7 (C), 151.7 (C), 145.8 (C), 140.4 (C), 139.9 (C), 129.9 (2×CH), 127.99 (C), 127.96 (CH), 127.6 (CH), 127.5 (CH), 127.4 (C), 126.3 (CH), 126.1 (CH), 126.0 (CH), 125.8 (CH), 123.3 (CH), 119.6 (CH), 118.7 (CH), 118.6 (CH), 114.2 (2×CH), 109.9 (CH), 84.5 (C), 65.4 (CH), 55.3 (CH3), 54.3 (CH3), 49.9 (CH2); IR (neat):1602 (s), 1512 (s), 1489 (s), 1462 (s), 1449 (s), 1248 (s).

2-Imidazoline 22. According to General Procedure I, reaction between p-methoxybenzylamine 12 (548 mg, 4.0 mmol), furfural 21 (388 mg, 4.0 mmol) and 4 (288 mg, 1.5 mmol), followed by column chromatography, afforded 22 (361 mg, 60%) as dark brown crystals. Mp 67.1–70.0 oC; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.61 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.36–7.13 (m, 8H), 7.08–7.03 (m, 1H), 6.95–6.91 (m, 2H), 6.12 (dd, J = 3.2, 1.8 Hz, 1H), 5.92 (d,

J = 4.2 Hz, 1H), 4.80 (s, 1H), 4.60 (d, J = 14.5 Hz, 1H), 4.07 (d, J = 14.5 Hz, 1H), 3.83 (s, 3H); 13C NMR (101 MHz): δ (ppm) 159.4 (C), 158.1 (CH), 149.8 (C), 149.5 (C), 144.9 (C), 142.0 (C), 140.1 (2×CH), 129.7 (CH), 128.5 (CH), 128.3 (CH), 127.9 (CH), 127.6 (C), 127.0 (CH), 125.7 (CH), 123.5 (CH), 119.6 (CH), 119.3 (CH), 114.2 (2×CH), 110.1 (CH), 108.6 (CH), 83.5 (C), 65.8 (CH), 55.3 (CH3), 49.7 (CH2); IR (KBr): 1609 (s), 1512 (s), 1248 (s); MS (EI, 70 eV) m/z (%) = 406 (28) [M]+, 285 (100), 165 (39), 121 (27), HRMS (EI, 70 eV) calculated for C27H22N2O2 (M+) 406.1681, found 406.1684.

N

N

MeO

N

NPMB

MeO

N

NPMB

OMe

N

NPMBO


53

2-Imidazoline 24. According to General Procedure I, reaction between p-methoxybenzylamine 12 (548 mg, 4.0 mmol), 5-methylfurfural 23 (440 mg, 4.0 mmol) and 4 (288 mg, 1.5 mmol), followed by column chromatography, afforded 24 (386 mg, 61%) as a dark brown oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.58 (s, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.31 (m, 1H), 7.26–7.19 (m, 6H), 7.10 (m, 1H), 6.93–6.90 (m, 2H), 5.75 (d, J = 3.1 Hz, 1H), 5.67 (m,

1H), 4.73 (s, 1H), 4.58 (d, J = 14.6 Hz, 1H), 4.08 (d, J = 14.6 Hz, 1H), 3.83 (s, 3H), 2.08 (s, 3H); 13C NMR (101 MHz): δ (ppm) 159.3 (C), 158.0 (CH), 151.7 (C), 149.8 (C), 147.5 (C), 145.2 (C), 140.2 (C), 140.1 (C), 129.6 (2×CH), 128.3 (CH), 128.1 (CH), 127.9 (C), 127.7 (CH), 126.7 (CH), 126.0 (CH), 123.4 (CH), 119.4 (CH), 119.1 (CH), 114.1 (2×CH), 109.7 (CH), 105.8 (CH), 83.5 (C), 65.9 (CH), 55.3 (CH3), 49.6 (CH2), 13.4 (CH3); IR (neat): 1593 (s), 1512 (s), 1248 (s).

2-Imidazoline 27. According to General Procedure I, reaction between furfurylamine 25 (291 mg, 3.0 mmol), ethyl-trans-4-oxo-butenoate 26 (384 mg, 3.0 mmol) and 4 (384 mg, 2.0 mmol), followed by column chromatography, afforded 27 (536 mg, 67%) as a light brown oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.64 (d, J = 7.4 Hz, 2H), 7.54 (d, J = 7.0 Hz, 2H), 7.50–7.18 (m, 6H), 6.48 (dd, J = 15.6, 7.9 Hz, 1H), 6.43 (m, 1H), 6.32 (d, J = 3.1 Hz, 1H), 5.67 (d, J = 15.7 Hz, 1H), 4.57 (d, J = 15.8 Hz, 1H), 4.26 (d, J = 8.0 Hz, 1H), 4.16 (d, J = 15.8 Hz,

1H), 4.06 (q, J = 7.1 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (63 MHz): δ (ppm) 165.1 (C), 158.9 (CH), 149.0 (C), 148.2 (C), 144.1 (C), 142.9 (CH), 142.3 (CH), 140.8 (C), 139.8 (C), 128.7 (CH), 127.8 (CH), 127.4 (CH), 125.6 (CH), 124.1 (CH), 124.0 (CH), 120.0 (CH), 119.6 (CH), 110.4 (CH), 109.5 (CH), 83.9 (C), 68.8 (CH), 60.3 (CH2), 42.9 (CH2), 14.0 (CH3); IR (neat): 1730 (s), 1715 (s), 1697 (s), 1682 (s), 1661 (s), 1182 (m).

2-Imidazoline 31. According to General Procedure I, reaction between allylamine 30 (570 mg, 10.0 mmol), isobutyraldehyde 8 (720 mg, 10.0 mmol) and 4 (1.0 g, 5.24 mmol), followed by flash column chromatography, afforded 31 (1.439 g, 91%) as a brown oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.60–7.55 (m, 2H), 7.36–7.12 (m, 7H), 5.97–5.84 (m, 1H), 5.35–5.28 (m, 2H), 3.96 (dd, J = 15.5, 4.7 Hz, 1H), 3.71 (dd, J = 15.5, 7.8 Hz, 1H), 3.56 (d, J = 8.2 Hz, 1H), 1.95–1.71 (m, 1H),

0.79 (d, J = 6.8 Hz, 3H), 0.19 (d, J = 6.7 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 160.4 (CH), 150.9 (C), 145.7 (C), 140.6 (C), 140.5 (C), 133.3 (CH), 128.3 (2×CH), 127.7 (CH), 127.0 (CH), 126.4 (CH), 124.4 (CH), 119.8 (CH), 119.7 (CH), 119.4 (CH2), 83.6 (C), 73.6 (CH), 51.4 (CH2), 29.9 (CH), 20.7 (CH3), 19.9 (CH3); IR (neat): 2960 (s), 2927 (m), 2869 (m), 1673 (s), 1609 (s), 1449 (s); HRMS (EI, 70 eV) calculated for C21H22N2 (M+) 302.1783, found 302.1779.

2-Imidazoline 34. According to General Procedure I, reaction between 2-aminoethanol 32 (122 mg, 2.0 mmol), p-formaldehyde 33 (60 mg, 2.0 mmol) and 4 (191 mg, 1.0 mmol), followed by flash column chromatography (EtOAc:MeOH:Et3N = 1:0:0.01, gradient), afforded 34 (218 mg, 83%) as a sticky yellow solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.58–7.55 (m, 4H), 7.36–7.17 (m, 5H), 3.51 (s, 2H), 3.44–3.40 (m, 2H), 3.36 (br s, 1H), 3.11 (t, J = 5.4 Hz, 2H); 13C

NMR (63 MHz, CDCl3): δ (ppm) 158.8 (CH), 149.7 (2×C), 139.8 (2×C), 129.1 (2×CH), 128.5 (2×CH), 124.0 (2×CH), 119.7 (2×CH), 79.2 (C), 59.1 (CH2), 58.6 (CH2), 49.4 (CH2); IR (neat): 3177 (s, br), 3044 (m), 2924 (m), 2854 (m), 1663 (s), 1590 (s), 1449 (s), 1067 (s); HRMS (EI, 70 eV) calculated for C17H16N2O (M+) 264.1263, found 264.1255.

2-Imidazoline 36. According to General Procedure I, reaction between p-methoxybenzylamine 12 (274 mg, 2.0 mmol), p-hydroxybenzaldehyde 35 (244 mg, 2.0 mmol) and 4 (191 mg, 1.0 mmol), followed by flash column chromatography (EtOAc:MeOH:Et3N = 1:0:0.01, gradient), afforded 36 (294 mg, 68%) as a yellow solid. Precipitation from ethyl acetate gave a white powder. Mp = 245–248 ºC; 1H NMR (400 MHz, pyridine-d5): δ (ppm) 11.28 (br s, 1H), 8.10 (s, 1H), 7.62–7.59 (m, 2H), 7.54 (s, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.36–7.29 (m, 4H), 7.17–7.08 (m, 2H), 7.03 (d, J =

N

NPMBO

N

N

EtO2C O

N

N

N

N

OH

N

NPMB

HO

Chapter 3

54

8.3 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 5.10 (s, 1H), 4.94 (br s, 1H), 4.76 (d, J = 14.4 Hz, 1H), 4.14 (d, J = 14.4 Hz, 1H), 3.68 (s, 3H); 13C NMR (101 MHz, pyridine-d5): δ (ppm) 160.0 (CH), 159.8 (C), 158.2 (C), 151.1 (C), 146.7 (C), 141.6 (C), 140.4 (C), 130.5 (2×CH), 128.8 (2×CH), 128.7 (CH), 128.6 (C), 128.3 (CH), 128.1 (CH), 127.2 (CH), 127.1 (CH), 125.8 (C), 125.0 (CH), 119.91 (CH), 119.86 (CH), 115.8 (2×CH), 114.6 (×CH), 85.6 (C), 72.9 (CH), 55.2 (CH3), 49.8 (CH2); IR (KBr): 3438 (s, br), 3035 (s), 2997 (s), 2928 (s), 1609 (s), 1588 (s), 1506 (s), 1249 (s); HRMS (EI, 70 eV) calculated for C29H24N2O2 (M+) 432.1838, found 432.1850.

2-Imidazoline 38. According to General Procedure I, reaction between 3-amino-1-propanol 37 (150 mg, 2.0 mmol), p-hydroxybenzaldehyde 35 (244 mg, 2.0 mmol) and 4 (191 mg, 1.0 mmol) in MeOH, followed by flash column chromatography (EtOAc:Et3N = 1:0.01, EtOAc:MeOH:Et3N = 1:0.01:0.01, gradient) and crystallisation from EtOAc and PE, afforded 38 (141 mg, 38%) as a white solid. Mp = 190–193 ºC; 1H NMR (250 MHz, DMSO-d6): δ (ppm) 9.12 (br s, 1H), 7.66 (s, 1H), 7.64–7.63 (m, 1H), 7.56–7.49 (m, 2H), 7.40–7.32 (m,

2H), 7.12–7.06 (m, 1H), 7.01–6.96 (m, 2H), 6.53 (d, J = 8.5 Hz, 2H), 6.36 (d, J = 8.5 Hz, 2H), 4.85 (s, 1H), 4.54 (br s, 1H), 3.50–3.45 (m, 2H), 3.43–3.31 (m, 1H), 3.04–2.94 (m, 1H), 1.74–1.64 (m, 2H); 13C NMR (63 MHz, DMSO-d6): δ (ppm) 159.8 (CH), 156.3 (C), 150.1 (C), 145.6 (C), 140.2 (C), 139.4 (C), 128.3 (CH), 127.8 (3×CH), 127.7 (CH), 126.4 (CH), 126.2 (CH), 125.3 (C), 124.2 (CH), 119.5 (CH), 119.3 (CH), 114.5 (2×CH), 84.2 (C), 72.5 (CH), 58.2 (CH2), 42.3 (CH2), 30.3 (CH2); IR (KBr): 3420 (s, br), 3057 (s), 2933 (s), 1660 (s), 1515 (s), 1447 (s), 1267 (s), 1232 (s), 1047 (s); HRMS (EI, 70 eV) calculated for C24H22N2O2 (M+) 370.1681, found 370.1690.

Bis-2-imidazoline 40. According to General Procedure I, reaction between hexane-1,6-diamine 39 (116 mg, 1.0 mmol), isobutyraldehyde 8 (144 mg, 2.0 mmol) and 4 (350 mg, 1.83 mmol), followed by flash column chromatography, afforded 40 (370 mg, 67%) as a yellow solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.68 (d, J = 7.3 Hz, 4H), 7.47–7.23 (m, 14H), 3.73 (d, J = 7.5 Hz, 2H), 3.43–3.27 (m, 4H), 2.00–1.80 (m, 6H), 1.70–1.50 (m, 4H), 0.89 (d, J = 6.8 Hz, 6H), 0.37 (d, J = 6.8 Hz, 6H);

13C NMR (63 MHz, CDCl3): δ (ppm) 160.2 (2×CH), 151.0 (2×C), 145.8 (2×C), 140.62 (2×C), 140.56 (2×C), 128.3 (4×CH), 127.7 (2×CH), 127.0 (2×CH), 126.5 (2×CH), 124.5 (2×CH), 119.8 (2×CH), 119.7 (2×CH), 83.4 (2×C), 73.8 (2×CH), 48.3 (2×CH2), 29.6 (2×CH), 27.8 (2×CH2), 27.2 (2×CH2), 20.4 (2×CH3), 20.1 (2×CH3); IR (neat): 2957 (s), 2932 (s), 2868 (m), 1605 (s), 1448 (s); HRMS (EI, 70 eV) calculated for C42H46N4 (M+) 606.3722, found 606.3779.

Bis-2-imidazoline 42. According to General Procedure I, reaction between isopropylamine 10 (118 mg, 2.0 mmol), isophtalaldehyde 41 (268 mg, 1.0 mmol) and 4 (382 mg, 2.0 mmol), followed by flash column chromatography, afforded 42 (329 mg, 55%) as a yellow solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.59 (s, 1H), 7.48 (s, 1H), 7.47–7.22 (m, 9H), 6.98–6.91 (m, 2H), 6.77–6.11 (m, 9H), 4.76

(s, 2H), 3.20–3.11 (m, 1H), 2.73 (br s, 1H), 1.53 (d, J = 6.9 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 156.3 (CH), 156.2 (CH), 150.2 (C), 149.9 (C), 145.1 (2×C), 140.7 (C), 140.4 (C), 140.0 (C), 139.8 (C), 135.74 (C), 135.68 (C), 128.4 (CH), 128.4 (CH), 127.90 (CH), 127.87 (CH), 127.8 (CH), 127.6 (CH), 127.3 (CH), 127.2 (CH), 126.25 (CH), 126.20 (CH), 126.16 (CH), 125.8 (CH), 125.7 (2×CH), 123.9 (CH), 123.8 (CH), 119.5 (CH), 119.4 (CH), 119.3 (CH), 119.0 (CH), 84.2 (C), 84.0 (C), 72.3 (CH), 72.1 (CH), 46.5 (CH), 46.4 (CH), 22.3 (CH3), 22.1 (CH3), 20.3 (CH3), 19.9 (CH3); IR (neat): 3041 (m), 2968 (s), 1585 (s), 1448 (s), 1225 (s), 1197 (s); HRMS (EI, 70 eV) calculated for C42H38N4 (M+) 598.3096, found 598.3074.

N

N

HOOH

N N

NN

N N N N


55

1-(Isocyanomethyl)-4-nitrobenzene 44a. Acetic formic anhydride (13 mL) was added drop wise to a stirred solution of 4-nitrobenzylamine 45 (6.7 g, 44.1 mmol) in 90 mL dry DCM at 0°C. Stirring was continued for 1 h at rt. Evaporation of the solvent and acids at reduced pressure yielded 46 as a white solid. 1H NMR (200 MHz, CDCl3): δ (ppm) 8.26 (s, 1H), 8.13 (d, J = 9.6 Hz, 2H), 7.41 (d, J = 9.6 Hz, 2H), 6.10 (br s, 1H), 4.59 (d, J = 7.6 Hz, 2H). To a stirred solution of crude 46 in 150 mL dry THF at –

78 °C, Et3N (34 ml, 240 mmol) was added. After this POCl3 (5.6 mL, 54 mmol) in 40 mL dry THF was added drop wise and the reaction mixture was allowed to warm to 0°C. After stirring for another 1 h, the reaction mixture was poured into ice cold water (100 mL). The mixture was extracted with Et2O (3 × 80 mL). Concentration in vacuo afforded 44a (7.0 g, 98% over 2 steps) as an almost pure, light brown solid. Mp = 98–101 ºC; 1H NMR (250 MHz, CDCl3): δ (ppm) 8.21 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 4.71 (s, 2H); 13C NMR (63 MHz, CDCl3): δ (ppm) 158.7 (C), 139.0 (C), 126.5 (2×CH), 124.2 (2×CH), 45.8 (C), 44.9 (t, J = 7.6 Hz, CH2); IR (neat): 2157 (s), 1516 (s), 1351 (s); HRMS (EI, 70 eV) calculated for C8H6N2O2 (M+) 162.0429, found 162.0432. General Procedure II for the AgOAc-catalysed synthesis of 2-imidazolines: Reactions were carried out at a concentration of 1 M of amine, 1 M of aldehyde and 0.5 M of isocyanide in dry DCM, unless stated otherwise. Na2SO4 and the aldehyde were added, at rt, to a stirred solution of the amine. After stirring for 2 h, the isocyanide and AgOAc (2 mol% relative to the isocyanide) were added and the reaction mixture was stirred at for an additional 18 h. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (PE:EtOAc:Et3N = 2:1:0.01, gradient).

1,5-Diisopropyl-4-(4-nitrophenyl)-4,5-dihydro-1H-imidazole 47. According to General Procedure II, reaction between isopropylamine 10 (144 mg, 2.0 mmol), isobutyraldehyde 8 (118 mg, 2.0 mmol) and 44a (162 mg, 1.0 mmol) gave 47 as a mixture of diastereomers, together with some 48. When the NMR sample was subjected to air, oxidation of the cis-diastereomer to imidazole 48 could be seen. Flash column chromatography afforded trans-47

(106 mg, 39%) as an orange oil and 48 (74 mg, 27%) as a sticky yellow solid. trans-47: 1H NMR (250 MHz, CDCl3): δ (ppm)8.12 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 1.2 Hz, 1H), 4.76 (d, J = 6.3 Hz, 1H), 3.40–3.29 (m, 1H), 3.28 (dd, J = 6.4, 3.8 Hz, 1H), 2.00–1.86 (m, 1H), 1.31 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 153.7 (CH), 152.6 (C), 146.9 (C), 127.5 (2×CH), 123.8 (2×CH), 71.2 (CH), 69.4 (CH), 46.3 (CH), 29.7 (CH), 22.2 (CH3), 22.0 (CH3), 17.8 (CH3), 15.6 (CH3); IR (neat): 2964 (m), 1592 (s), 1519 (s), 1344 (s); HRMS (EI, 70 eV) calculated for C15H21N3O2 (M+) 275.1634, found 275.1625.

1,5-Diisopropyl-4-(4-nitrophenyl)-1H-imidazole 48. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.21 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.60 (s, 1H), 4.48 (m, 1H), 3.38 (m, 1H), 1.54 (d, J = 6.8 Hz, 6H), 1.34 (d, J = 7.3 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ (ppm) 146.1 (C), 142.9 (C), 135.0 (C), 134.1 (CH), 133.7 (C), 128.9 (2×CH), 123.4 (2×CH), 47.4 (CH), 24.8 (CH), 24.3 (2×CH3), 21.7 (2×CH3); IR (neat): 2971 (m), 2934 (m), 1597 (s), 1515

(s), 1343 (s); HRMS (EI, 70 eV) calculated for C15H19N3O2 (M+) 273.1477, found 273.1478.

1-(4-Methoxybenzyl)-5-(4-methoxyphenyl)-4-(4-nitrophenyl)-4,5-dihydro-1H-imidazole 54. According to General Procedure II, reaction between p-methoxybenzylamine 12 (274 mg, 2.0 mmol), p-anisaldehyde 16 (272 mg, 2.0 mmol) and 44a (162 mg, 1.0 mmol), followed by flash column chromatography, afforded 54 (293 mg, 70%) as a 29:71 mixture of diastereomers as an orange/brown oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 8.14 (d, J = 8.6 Hz, 2H), 7.93 (d, J = 8.6 Hz, 2H), 7.452 (s, 1H), 7.448 (s, 1H), 7.32–6.84 (6H + 10H), 6.76

(d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 5.53 (d, J = 11.4 Hz, 1H), 5.06 (d, J = 10.4 Hz, 1H), 4.77 (d, J = 11.3 Hz, 1H), 4.48 (d, J = 14.5 Hz, 1H), 4.38 (d, J = 14.3 Hz, 1H), 3.99 (d, J = 10.2 Hz, 1H), 3.90–3.78 (m, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.72 (s, 3H); 13C NMR (101 MHz, CDCl3): δ (ppm) 159.7 (C), 159.32 (C),

NO2

NC

N

N

O2N

N

N

O2N

N

NPMB

O2N

M2O

Chapter 3

56

159.29 (C), 159.0 (C), 157.9 (CH), 156.7 (CH), 150.6 (C), 147.3 (C), 147.2 (C), 146.5 (C), 131.2 (C), 129.5 (2×CH), 129.4 (2×CH), 129.1 (2×CH), 128.7 (2×CH + 2×CH), 127.8 (C), 127.4 (2×CH), 126.8 (C), 123.7 (2×CH), 122.6 (2×CH), 114.8 (2×CH), 114.2 (2×CH + 2×CH), 113.6 (2×CH), 79.2 (CH), 74.0 (CH), 71.4 (CH), 66.9 (CH), 55.31 (CH3), 55.28 (CH3), 55.24 (CH3), 55.1 (CH3), 48.8 (CH2), 48.6 (CH2), One quaternary C of the minor diastereomer (trans) could not be detected. Relative stereochemistry was assigned using gs-HMBC and gs-NOESY measurements; IR (neat): 1610 (s), 1594 (s), 1513 (s), 1344 (s), 1248 (s); HRMS (EI, 70 eV) calculated for C24H23N3O4 (M+) 417.1689, found 417.1681. After storing the product for about 6 months under air, only the corresponding imidazole 55 (a yellow solid) was retrieved

1-(4-Methoxybenzyl)-5-(4-methoxyphenyl)-4-(4-nitrophenyl)-1H-imidazole 55. Mp = 172–178 ºC 1H NMR (250 MHz, CDCl3): δ (ppm) 7.97 (d, J = 9.1 Hz, 2H), 7.58–7.53 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 6.90–6.82 (m, 4H), 6.74 (d, J = 8.8 Hz, 2H), 4.80 (s, 2H), 3.80 (s, 3H), 3.71 (s, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 160.4 (C), 159.4 (C), 145.7 (C), 141.4 (C), 137.4 (CH), 136.2 (C), 132.0 (2×CH), 131.2 (C), 128.5 (2×CH), 128.0 (C), 126.3 (2×CH), 123.6 (2×CH), 121.5 (C), 114.8 (2×CH), 114.2 (2×CH), 55.32 (CH3), 55.27 (CH3),

48.4 (CH2); IR (neat): 1612 (m), 1598 (m), 1513 (s), 1333 (s), 1250 (s), 1176 (m), 1100 (m), 1028 (m); HRMS (EI, 70 eV) calculated for C24H21N3O4 (M+) 415.1532, found 415.1518.

1-(4-Methoxybenzyl)-5-isopropyl-4-(4-nitrophenyl)-4,5-dihydro-1H-imidazole 56. According to General Procedure II, reaction between p-methoxybenzylamine 12 (274 mg, 2.0 mmol), isobutyraldehyde 8 (118 mg, 2.0 mmol) and 44a (162 mg, 1.0 mmol) gave 56 as a mixture of diastereomers, together with some of the corresponding imidazole 57. Flash column chromatography afforded trans-56 (150 mg, 42%) as an orange oil and the 57 (40

mg, 11%) as a colourless oil. trans-56: 1H NMR (250 MHz, CDCl3): δ (ppm) 8.12 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 7.16–7.13 (m, 3H), 6.89 (d, J = 8.6 Hz, 2H), 4.86 (d, J = 6.8 Hz, 1H), 4.51 (d, J = 14.9 Hz, 1H), 4.12 (d, J = 14.9 Hz, 1H), 3.82 (s, 3H), 3.20 (dd, J = 6.9, 3.8 Hz, 1H), 2.10–1.93 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 159.8 (C), 156.9 (CH), 152.7 (C), 147.3 (C), 129.6 (2×CH), 128.4 (C), 128.1 (2×CH), 124.1 (2×CH), 114.6 (2×CH), 71.1 (CH), 70.8 (CH), 55.7 (CH3), 49.2 (CH2), 29.4 (CH), 18.3 (CH3), 16.6 (CH3); IR (neat): 2959 (m), 1595 (s), 1514 (s), 1345 (s), 1248 (s); HRMS (EI, 70 eV) calculated for C20H23N3O3 (M+) 353.1739, found 353.1749.

1-(4-Methoxybenzyl)-5-isopropyl-4-(4-nitrophenyl)-1H-imidazole 57. 1H NMR (250 MHz, CDCl3): δ (ppm) 8.16 (d, J = 8.9 Hz), 2H), 7.64 (d, J = 8.9 Hz, 2H), 7.35 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 5.08 (s, 2H), 3.73 (s, 3H), 3.22–3.29 (m, 1H), 1.17 (d, J = 7.3 Hz, 6H); 13C NMR (63 MHz, CDCl3): δ (ppm) 159.5 (C), 146.3 (C), 142.9 (C), 137.8 (CH), 136.3 (C), 134.7 (C), 129.0 (2×CH), 128.1 (2×CH), 127.9 (C), 123.4

(2×CH), 114.4 (2×CH), 55.3 (CH3), 49.1 (CH2), 24.7 (CH), 21.7 (2×CH3); IR: 2966 (m), 2934 (m), 1598 (m), 1514 (s), 1343 (s), 1249 (s); HRMS (EI, 70 eV) calculated for C20H21N3O3 (M+) 351.1583, found 351.1600.

2-Imidazoline 63. According to General Procedure II, reaction between benzylamine 71 (214 mg, 2.0 mmol), cyclohexanone 62 (196 mg, 2.0 mmol) and 4 (191 mg, 1.0 mmol), followed by flash column chromatography, afforded 63 (76 mg, 20%) as a brown oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.55–7.49 (m, 2H), 7.42–7.10 (m, 12H), 4.23 (s, 2H), 2.07–1.98 (m, 2H), 1.42–1.30 (m, 2H), 1.10–1.05 (m, 3H), 0.80–0.72 (m, 1H), 0.37–0.26 (m, 2H); 13C NMR (63 MHz,

CDCl3): δ (ppm) 159.1 (CH), 147.7 (2×C), 140.6 (2×C), 138.8 (2×C), 128.8 (CH), 128.1 (2×CH), 127.7 (2×CH), 127.6 (CH), 126.6 (2×CH), 126.1 (2×CH), 119.7 (2×CH), 85.2 (C), 69.3 (C), 46.0 (CH2), 32.5 (CH2), 24.9 (2×CH2), 22.7 (2×CH2); IR (neat): 3061 (m), 3030 (m), 2932 (s), 2861 (m), 1675 (m), 1595 (s), 1449 (s); HRMS (EI, 70 eV) calculated for C27H26N2 (M+) 378.2096, found 378.2105.

N

NPMB

O2N

M2O

N

NPMB

O2N

N

NPMB

O2N

N

N

Ph


57

2-Imidazoline 64. According to General Procedure II, reaction between benzylamine 71 (214 mg, 2.0 mmol), cyclohexanone 62 (196 mg, 2.0 mmol) and 60 (185 mg, 1.05 mmol), followed by flash column chromatography, afforded 64 (212 mg, 55%) as a green/brown oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.87–7.83 (m, 2H), 7.39–7.24 (m, 8H), 7.11 (s, 1H), 4.48 (s, 2H),

3.77 (s, 3H), 2.14–2.06 (m, 1H), 1.82–1.50 (m, 2H), 1.44–1.12 (m, 6H), 0.91–0.89 (m, 1H); 13C NMR (63 MHz, CDCl3): δ (ppm) 172.5 (C), 156.7 (CH), 138.7 (C), 137.2 (C), 128.8 (2×CH), 128.66 (CH), 128.65 (CH), 127.6 (2×CH), 127.5 (2×CH), 127.2 (2×CH), 85.2 (C), 70.9 (C), 52.3 (CH3), 47.9 (CH2), 31.9 (CH2), 31.4 (CH2), 24.8 (CH2), 22.5 (CH2) 21.8 (CH2); IR (neat): 2926 (s), 1726 (s), 1605 (s), 1452 (s), 1238 (s), 1218 (s); HRMS (EI, 70 eV) calculated for C23H26N2O2 (M+) 362.1994, found 362.1996.

2-Imidazoline 65. According to General Procedure II, reaction between benzylamine 71 (214 mg, 2.0 mmol), cyclohexanone 62 (196 mg, 2.0 mmol) and 44a (162mg, 1.0 mmol), followed by flash column chromatography, afforded 65 (267 mg, 77%) as a brown solid. Mp = 130–136 ºC; 1H NMR (250 MHz, CDCl3): δ (ppm) 8.09 (d, J = 8.8 Hz, 2H), 7.38–7.19 (m, 7H), 6.99 (s, 1H), 4.95 (s, 1H), 4.24 (d, J = 15.2 Hz, 1H), 4.14 (d, J = 15.2 Hz, 1H), 1.81–0.69 (m, 10H); 13C NMR (63 MHz, CDCl3): δ (ppm): 156.2 (CH), 147.2 (C), 147.0 (C),

138.3 (C), 129.6 (2×CH), 128.8 (2×CH), 127.7 (CH), 127.6 (2×CH), 123.1 (2×CH), 76.5 (CH), 67.4 (C), 45.6 (CH2), 33.8 (CH2), 30.2 (CH2), 24.9 (CH2), 23.1 (CH2), 21.9 (CH2); IR (neat):2934 (s), 2855 (m), 1595 (s), 1518 (s), 1345 (s); HRMS (EI, 70 eV) calculated for C21H23N3O2 (M+) 349.1790, found 349.1790.

2-Imidazoline 67. According to General Procedure II, reaction between benzylamine 71 (214 mg, 2.0 mmol), acetone 66 (116 mg, 2.0 mmol) and 4 (191 mg, 1.0 mmol), followed by flash column chromatography, afforded 67 (244 mg, 72%) as a white solid. Mp = 138–145 ºC; 1H NMR (250 MHz, CDCl3): δ (ppm) 7.65 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 7.6 Hz, 2H), 7.45–7.21 (m, 10H), 4.32 (s, 2H), 1.11 (s, 6H); 13C NMR (63 MHz, CDCl3): δ (ppm) 158.2 (CH), 147.0

(2×C), 141.2 (2×C), 137.6 (C), 128.6 (2×CH), 128.1 (2×CH), 128.0 (2×CH), 127.5 (CH), 126.5 (2×CH), 125.9 (2×CH), 119.5 (2×CH), 85.4 (C), 68.9 (C), 46.6 (CH2), 22.6 (2×CH3); IR (neat): 3062 (s), 3031 (s), 2969 (s), 2927 (s), 2865 (m), 1674 (s), 1589 (s), 1462 (s), 1449 (s), 1385 (s), 1365 (s), 1263 (s), 1226 (s), 1153 (s); HRMS (EI, 70 eV) calculated for C24H22N2 (M+) 338.1783, found 338.1793.

Methyl 1-benzyl-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 68. According to General Procedure II, reaction between benzylamine 71 (214 mg, 2.0 mmol), acetone 66 (116 mg, 2.0 mmol) and 60 (175 mg, 1.0 mmol), followed by flash column chromatography, afforded 68 (201 mg, 62%) as a yellow oil. 1H NMR (250 MHz, CDCl3): δ

(ppm) 7.67–7.63 (m, 2H), 7.41–7.26 (m, 8H), 7.17 (s, 1H), 4.22 (s, 2H), 3.78 (s, 3H), 1.42 (s, 3H), 0.86 (s, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 172.0 (C), 156.3 (CH), 138.0 (C), 137.0 (C), 128.7 (2×CH), 127.7 (2×CH), 127.62 (3×CH), 127.60 (CH), 127.5 (2×CH), 84.4 (C), 69.1 (C), 51.9 (CH3), 46.0 (CH2), 22.8 (CH3), 22.2 (CH3); IR (neat): 2924 (m), 1728 (s), 1600 (s), 1263 (s), 1231 (s); HRMS (EI, 70 eV) calculated for C20H22N2O2 (M+) 322.1681, found 322.1683.

1-Benzyl-5,5-dimethyl-4-(4-nitrophenyl)-4,5-dihydro-1H-imidazole 69. According to General Procedure II, reaction between benzylamine 71 (214 mg, 2.0 mmol), acetone 66 (116 mg, 2.0 mmol) and 44a (162 mg, 1.0 mmol), followed by flash column chromatography, afforded 69 (207 mg, 67%) as a brown oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 8.23 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.45–7.29 (m, 5H), 7.05 (d, J = 1.3

Hz, 1H), 4.95 (s, 1H), 4.31 (d, J = 15.0 Hz, 1H), 4.21 (d, J = 15.0 Hz, 1H), 1.42 (s, 3H), 0.67 (s, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 156.4 (CH), 147.4 (C), 147.3 (C), 137.8 (C), 128.8 (2×CH), 128.6 (2×CH), 127.8 (CH), 127.6 (2×CH), 123.3 (2×CH), 79.4 (CH), 66.0 (C), 46.4 (CH2), 27.2 (CH3), 21.0 (CH3); IR (neat): 1593 (s), 1518 (s), 1346 (s); HRMS (EI, 70 eV) calculated for C18H19N3O2 (M+) 309.1477, found 309.1479.

N

N

Ph

MeO2CPh

N

N

Ph

O2N

N

N

Ph

N

N

Ph

MeO2CPh

N

N

Ph

O2N

Chapter 3

58

2-Imidazoline 72. According to General Procedure I, reaction between benzylamine 71 (214 mg, 2.0 mmol), 3-(chloromethyl)cyclobutanone 70 (237 mg, 2.0 mmol) and 4 (191 mg, 1.0 mmol), followed by flash column chromatography, afforded 72 (252 mg, 63%) as a 60:40 mixture of isomers as a light brown solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.59–7.56 (m, 2H + 2H), 7.39–7.13 (m, 12H + 12H), 4.55 (s, 2H), 4..43 (s, 2H), 3.14 (d, J = 5.3 Hz, 2H), 2.80

(d, J = 6.8 Hz, 2H), 2.35–2.00 (m, 3H + 4H), 1.72–1.63 (m, 2H), 1.25–1.15 (m, 1H); 13C NMR (63 MHz, CDCl3): δ (ppm) 157.9 (CH), 157.7 (CH), 146.1 (2×C), 145.6 (2×C), 140.53 (2×C), 140.52 (2×C), 138.0 (C), 137.9 (C), 129.5 (2×CH), 129.4 (2×CH), 129.03 (2×CH), 128.97 (2×CH), 128.5 (2×CH), 128.3 (CH), 128.2 (CH), 128.1 (2×CH), 127.8 (2×CH), 127.6 (2×CH), 125.34 (2×CH), 125.28 (2×CH), 120.01 (2×CH), 119.95 (2×CH), 85.8 (C), 84.8 (C), 69.0 (C), 68.2 (C), 48.8 (CH2), 48.7 (CH2), 47.6 (CH2), 46.9 (CH2), 34.4 (2×CH2), 32.2 (2×CH2), 29.3 (CH), 28.1 (CH); Assignment of relative stereochemistry was achieved using gs-NOESY measurements; IR (KBr): 3029, (s), 2948 (s), 2914 (s), 2802 (s), 2749 (s), 2697 (s), 1598 (s), 1451 (s), 737 (s); HRMS (EI, 70 eV) calculated for C26H23ClN2 (M+) 398.1550, found 398.1540.

2-Imidazoline 73. According to General Procedure I, reaction between benzylamine 71 (214 mg, 2.0 mmol), 3-(chloromethyl)cyclobutanone 70 (237 mg, 2.0 mmol) and 60 (175 mg, 1.0 mmol), followed by flash column chromatography, afforded 73 (208 mg, 54%) as a 56:44 mixture of isomers as a yellow/brown oil. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.58–6.82 (m,

11H + 11H), 4.47 (d, J = 2.2 Hz, 2H), 4.43 (s, 2H), 3.67 (s, 3H), 3.65 (s, 3H), 3.35–3.22 (m, 2H), 3.20 (d, J = 5.4 Hz, 2H), 2.68–2.56 (m, 1H), 2.55–2.35 (m, 3H + 1H), 2.30–2.19 (1H), 1.96–1.82 (m, 1H + 1H), 1.80–1.68 (m, 1H), 1.49–1.43 (m, 1H); 13C NMR (63 MHz, CDCl3): δ (ppm) 173.9 (C), 171.6 (C), 156.8 (CH), 156.5 (CH), 138.1 (C), 137.9 (C), 137.8 (C), 137.7 (C), 128.9 (2×CH), 128.8 (2×CH), 128.3 (2×CH), 128.1 (2×CH), 127.9 (4×CH), 127.7 (CH), 127.4 (CH), 127.3 (2×CH), 127.2 (CH), 127.1 (CH), 126.8 (2×CH), 84.8 (C), 84.6 (C), 70.3 (C), 68.7 (C), 52.30 (CH3), 52.27 (CH3), 49.1 (CH2), 49.7 (CH2), 47.1 (CH2), 46.4 (CH2), 34.1 (CH2), 33.9 (CH2), 32.6 (CH2), 31.7 (CH2), 30.7 (CH), 28.2 (CH); Assignment of relative stereochemistry was achieved using gs-NOESY measurements; IR (neat): 3032 (m), 2954 (m), 2868 (m), 1743 (s), 1672 (s), 1634 (s), 1496 (s), 1455 (s), 1258 (s), 1215 (s), 1175 (s), 699 (s); HRMS (EI, 70 eV) calculated for C22H23ClN2O2 (M+) 382.1397, found 382.1428.

2-Imidazoline 76. According to General Procedure I, reaction between (R)-α-phenyl-ethylamine 75 (242 mg, 2.0 mmol), isobutyraldehyde 8 (144 mg, 2.0 mmol) and 4 (191 mg, 1.0 mmol), followed by flash column chromatography, afforded 76 (349 mg, 97%) as a 63:37 mixture of isomers as an orange solid. The same reaction in MeOH gave 76 (325 mg, 89%) as a 77:23 mixture of diastereomers. Separation of the diastereomers by column chromatography is possible. Diastereomer A (least polar): 1H NMR (250 MHz, CDCl3): δ (ppm) 7.76–7.24 (m,

14H), 4.67 (q, J = 6.8 Hz, 1H), 3.91 (d, J = 7.2 Hz, 1H), 2.09–2.01 (m, 1H), 1.75 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H), 0.45 (d, J = 6.8 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 145.7 (CH), 150.9 (C), 145.7 (C), 141.7 (C), 140.7 (C), 140.6 (C), 128.8 (2×CH), 128.4 (2×CH), 127.7 (CH), 127.6 (CH), 127.1 (2×CH), 127.0 (CH), 126.6 (CH), 124.3 (CH), 119.8 (CH), 119.8 (CH), 83.1 (C), 73.2 (CH), 55.0 (CH), 29.4 (CH), 20.2 (CH3), 20.1 (CH3), 16.7 (CH3); Diastereomer B (most polar): 1H NMR (250 MHz, CDCl3): δ (ppm) 7.92 (s, 1H), 7.70–7.22 (m, 11H), 7.15–7.09 (m, 1H), 6.69 (d, J = 7.5 Hz, 1H), 4.50 (q, J = 7.2 Hz, 1H), 3.47 (d, J = 7.1 Hz, 1H), 2.06–1.88 (m, 1H), 1.86 (d, J = 7.2 Hz, 3H), 0.77 (d, J = 6.9 Hz, 3H), 0.40 (d, J = 6.9 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 156.0 (CH), 151.3 (C), 146.0 (C), 140.7 (C), 140.6 (C), 140.2 (C), 129.0 (2×CH), 128.2 (CH), 128.1 (CH), 127.9 (CH), 127.6 (CH), 127.0 (2×CH), 126.9 (CH), 126.8 (CH), 124.4 (CH), 119.7 (CH), 119.4 (CH), 82.8 (C), 71.9 (CH), 57.1 (CH), 29.0 (CH), 22.1 (CH3), 19.7 (CH3), 19.6 (CH3); HRMS (mixture of diastereomers) (EI, 70 eV) calculated for C26H26N2 (M+) 366.2096, found 366.2092.

N

N

PhCl

N

N

PhCl

MeO2CPh

N

N

Ph


59

2-Imidazoline 77. According to General Procedure I, reaction between (R)-α-phenyl-ethylamine 75 (242 mg, 2.0 mmol), p-anisaldehyde 16 (272 mg, 2.0 mmol) and 4 (191 mg, 1.0 mmol), followed by flash column chromatography, afforded 77 (326 mg, 77%) as a 56:44 mixture of isomers as a pale orange solid. The same reaction in MeOH gave 77 (227 mg, 53%) as a 48:52 mixture of diastereomers. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.93 (s, 1H), 7.49–6.87 (m, 14H + 13H), 6.74 (d, J = 8.5 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 6.50–6.45 (m, 2H + 2H), 4.98 (s, 1H), 4.53 (s, 1H), 4.41 (q, J = 6.9 Hz, 1H), 4.15 (q, J = 7.3 Hz, 1H),

3.56 (s, 3H), 3.55 (s, 3H), 1.78 (d, J = 7.3 Hz, 3H), 1.50 (d, J = 6.9 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 158.8 (C), 158.6 (C), 158.0 (CH), 155.4 (CH), 150.1 (C), 149.8 (C), 145.4 (C), 144.9 (C), 140.9 (C), 140.8 (C), 140.7 (C), 140.6 (C), 139.9 (C), 139.8 (C), 128.9 (2×CH), 128.8 (2×CH), 128.4 (CH), 128.2 (2×CH + 1×CH), 127.9 (2×CH + 3×CH), 127.8 (CH), 127.7 (CH), 127.63 (CH), 127.60 (2×C), 127.4 (2×CH), 126.6 (2×CH + 1×CH), 126.6 (CH), 126.22 (CH), 126.18 (CH), 124.0 (CH), 123.9 (CH), 119.4 (CH), 119.3 (CH), 119.3 (CH), 119.2 (CH), 113.2 (2×CH), 113.2 (2×CH), 84.5 (C), 84.2 (C), 72.3 (CH), 72.0 (CH), 55.5 (CH), 54.99 (CH3), 54.97 (CH3), 54.2 (CH), 21.6 (CH3), 17.5 (CH3); IR (neat): 1593 (s), 1581 (s), 1512 (s), 1449 (s), 1248 (s), 1172 (s); HRMS (EI, 70 eV) calculated for C30H26N2O (M+) 430.2045, found 430.2039.

2-Imidazoline 79. According to General Procedure I, reaction between isopropylamine 10 (118 mg, 2.0 mmol), (R)-(−)-myrtenal 78 (300 mg, 2.0 mmol) and 4 (191 mg, 1.0 mmol), followed by flash column chromatography, afforded 79 (302 mg, 81%) as a 37:63 mixture of isomers as a pink/white foam. The same reaction in MeOH gave 79 (320 mg, 86%) as a 83:17 mixture of diastereomers. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.64–7.56 (m, 3H + 3H), 7.51–7.24 (m, 6H + 6H), 5.39 (dd, J = 2.9, 1.5 Hz, 1H), 4.94 (br s, 1H), 4.53 (s, 1H), 4.35 (d, J = 1.6 Hz, 1H),

3.46–3.36 (m, 1H), 3.23–3.12 (m, 1H), 2.10–2.06 (m, 2H), 2.00–1.62 (m, 5H + 3H), 1.51 (d, J = 7.0 Hz, 3H), 1.46 (d, J = 7.0 Hz, 3H), 1.30–1.21 (m, 1H), 1.27 (d, J = 6.3 Hz, 3H), 1.25 (d, J = 6.1 Hz, 3H), 1.13–1.08 (m, 1H), 1.09 (s, 3H), 0.94 (s, 3H), 0.52 (s, 3H), 0.51 (s, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 156.9 (CH), 156.6 (CH), 151.2 (C), 150.2 (C), 146.8 (C), 146.4 (C), 142.7 (C), 142.2 (C), 141.9 (C), 141.2 (C), 140.8 (C), 140.5 (C), 128.6 (CH + CH), 128.5 (CH), 128.4 (CH), 128.0 (CH), 127.9 (CH), 127.5 (CH), 127.4 (CH), 127.1 (CH), 126.5 (CH), 124.8 (CH), 124.5 (CH), 122.3 (CH), 119.9 (CH), 119.8 (CH), 119.7 (CH + CH), 119.4 (CH), 83.6 (C), 82.8 (C), 75.4 (CH), 73.8 (CH), 47.2 (CH), 46.6 (CH), 43.9 (CH), 43.8 (CH), 40.9 (CH), 40.2 (CH), 38.3 (C), 37.6 (C), 32.2 (CH2), 31.52 (CH2), 31.48 (CH2), 30.3 (CH2), 26.7 (CH3), 26.3 (CH3), 22.9 (CH3), 22.7 (CH3), 21.3 (CH3), 20.7 (CH3), 20.1 (CH3), 19.8 (CH3); HRMS (EI, 70 eV) calculated for C27H30N2 (M+) 328.2409, found 382.2399.

2-Imidazoline 80. According to General Procedure I, reaction between p-methoxybenzylamine 27 (274 mg, 2.0 mmol), (R)-(−)-myrtenal 78 (300 mg, 2.0 mmol) and 4 (191 mg, 1.0 mmol), followed by flash column chromatography, afforded 80 (345 mg, 75%) as a 55:45 mixture of isomers as a white foam. The same reaction in MeOH gave 80 (309 mg, 67%) as a 95:5 mixture of diastereomers. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.62–7.57 (m, 3H + 3H), 7.40–7.18 (m, 8H + 7H), 7.09 (d, J = 7.3 Hz, 1H), 7.00–6.96 (m, 2H + 2H), 5.53 (br s, 1H), 5.01 (br s, 1H),

4.62 (d, J = 14.6 Hz, 1H), 4.46 (d, J = 14.4 Hz, 1H), 4.29 (s, 1H), 4.11 (d, J = 14.6 Hz, 1H), 4.08 (s, 1H), 3.95 (d, J = 14.4 Hz, 1H), 3.88 (s, 6H), 2.19–1.63 (m, 6H + 5H), 1.10 (s, 3H), 1.04–1.00 (m, 1H), 0.94 (s, 3H), 0.60 (s, 3H), 0.53 (s, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 159.7 (CH), 159.33 (C), 159.27 (C), 159.2 (CH), 150.5 (C), 149.4 (C), 146.2 (C), 145.8 (C), 141.7 (C), 141.3 (C + C), 140.6 (C), 140.4 (C), 140.1 (C), 129.8 (2×CH), 129.7 (2×CH), 128.21 (CH), 128.18 (CH), 128.16 (CH), 128.1 (CH), 127.7 (C + C), 127.6 (CH), 127.5 (CH), 127.0 (CH + CH), 126.7 (CH), 126.1 (CH), 124.3 (CH), 124.2 (CH), 121.9 (CH), 119.4 (CH + CH), 119.3 (CH), 119.2 (CH), 118.8 (CH), 114.2 (2×CH), 114.1 (2×CH), 83.6 (C), 82.8 (C), 74.2 (CH), 72.2 (CH), 55.3 (2×CH3), 50.2 (CH2), 49.9 (CH2), 43.6 (CH), 43.3 (CH), 40.5 (CH), 39.8 (CH), 37.7 (C), 37.2 (C), 31.8 (CH2), 31.07 (CH2), 31.05 (CH2), 29.7 (CH2), 26.2 (CH3), 25.8 (CH3), 21.1 (CH3), 20.6 (CH3); HRMS (EI, 70 eV) calculated for C32H32N2O (M+) 460.2515, found 460.2500.

N

N

Ph

MeO

N

N

N

NPMB

Chapter 3

60


[1] Bordwell, F. G. Acc. Chem. Res. 1988, 21 456–463. [2] It is important to notice that combination of 4 with 10, 8, and propionic acid gives exclusive formation of

2-imidazoline 11 (70%). However, a similar reaction but now with benzhydrylamine 7 instead of isopropylamine 10 as amine input gives no 2-imidazoline. Instead, the bisamide, resulting from an Ugi-4CC, is formed as the only reaction product in 67%.

[3] The first example of a rhodium-catalysed direct C–H insertion of 4,4-dimethyl-2-imidazoline to 3,3-dimethylbut-1-ene was reported in: Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 1685–1687.

[4] Mammen, M.; Choi, S.-K.; Whitesides, G. M. Angew. Chem. Int. Ed. 1998, 37, 2754–2794 and references therein.

[5] Katayama, S.; Ae, N.; Kodo, T.; Masumoto, S.; Hourai, S.; Tamamura, C.; Tanaka, H.; Nagata, R. J. Med. Chem. 2003, 46, 691–701.

[6] For examples see: (a) Fehlhammer, W. P.; Bartel, K.; Petri, W. J. Organomet. Chem. 1975, 87, C34–C36. (b) Fehlhammer, W. P.; Zinner, G.; Bakola-Christianopoulou, M. J. Organomet. Chem. 1987, 331, 193–205.

[7] For examples see: (a) Soloshonok, V. A.; Kacharov, A. D.; Avilov, D. V.; Ishikawa, K.; Nagashima, N.; Hayashi, T. J. Org. Chem. 1997, 62, 3470–3479 and references cited therein.

[8] Saegusa, T.; Ito, Y.; Kinoshita, H.; Tomita, S. J. Org. Chem. 1971, 36, 3316–3323. [9] Saegusa, T.; Murase, I.; Ito, Y. Bull. Chem. Soc. Jap. 1972, 45, 830–833. [10] Dai, L.-X.; Lin, Y.-R.; Hou, X.-L.; Zhou, Y.-G. Pure Appl. Chem. 1999, 71, 1033–1040 and references cited

therein. [11] Grigg, R.; Lansdell, M. I.; Thornton-Pett, M. Tetrahedron 1999, 55, 2025–2044. [12] A second byproduct, isolated in only 7%, was characterised as the oxazoline formed by reaction of 42a and 6. [13] For a recent example of the air oxidation of imidazolines to imidazoles see: Illgen, K.; Nerdinger, S.;

Behnke, D.; Friedrich, C. Org. Lett. 2005, 7, 39–42. [14] Koch, W.; Holthausen, M. C. A Chemist’s Guide to Density Functional Theory; Wiley-VCH: Weinheim, 2000. [15] Also Cu2O was tried as catalyst, but still no reaction was observed. [16] Also p-fluorobenzyl isocyanide was tried as the isocyanide component in the reaction displayed in Scheme

9a. All conditions we tried only afforded the imine from 10 and 14 and the isocyanide. [17] Bickelhaupt, F. M.; Buisman, G. J. H.; de Koning, L. J.; Nibbering, N. M. M.; Baerends, E. J. J. Am. Chem.

Soc. 1995, 117, 9889–9899. [18] Swart, M., Bickelhaupt, F. M. J. Chem. Theory Comput. 2006, 2, 281–287. [19] a) Klamt, A.; Schüürmann, G. J. Chem. Soc., Perkin Trans. 2 1993, 799–805. b) Pye, C. C.; Ziegler, T.

Theor. Chem. Acc. 1999, 101, 396–408. [20] a) Stevens, C. V.; de Kimpe, N. J. Org. Chem. 1996, 61, 2174–2178. b) Rammeloo, T.; Stevens, C. V.; de

Kimpe, N. J. Org. Chem. 2002, 67, 6509–6513. [21] Application of the almost pure imine from 48 and 41 (prepared using TiCl4 (see reference 20b) resulted in

even higher yields for 73a (42%) and 73b (33%). [22] Juaristi, E.; Léon-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron: Asymmetry 1999, 10 2441–2495. [23] a) Johnson, F.; Malhotra, S. K. J. Am. Chem. Soc. 1965, 87, 5492–5493. b) Hoffmann, R. W. Chem. Rev. 1989,

89, 1841–1860. c) Broeker, J. L.; Hoffmann, R. W.; Houk, K. N. J. Am. Chem. Soc. 1991, 113, 5006–5017. [24] Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org. Chem. 2000, 65, 1516–1524. [25] a) te Velde, G.; Bickelhaupt, F. M.; Baerends, E. J.; Fonseca Guerra, C.; van Gisbergen, S. J. A.; Snijders, J.

G.; Ziegler, T. J. Comput. Chem. 2001, 22, 931–967. b) Fonseca Guerra, C.; Snijders, J. G.; te Velde, G.; Baerends, E. J. Theor. Chem. Acc. 1998, 99, 391–403. c) ADF 2004.01; SCM, Theoretical Chemistry, Vrije Universiteit, Amsterdam, The Netherlands, http://www.scm.com.

[26] van Lenthe, E.; Baerends, E. J. J. Comput. Chem. 2003, 24, 1142–1156. [27] van Lenthe, E.; Baerends, E. J.; Snijders, J. G. J. Chem. Phys. 1993, 99, 4597–4610. [28] Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200–1211.


61

[29] Becke, A. D. Phys. Rev. A 1988, 38, 3098–3100. [30] Perdew, J. P. Phys. Rev. B 1986, 33, 8822–8824. Erratum: Ibid. 1986, 34, 7406–7406. [31] Swart, M.; Snijders, J. G. Theor. Chem. Acc. 2003, 110, 34–41. [32] Jensen, F. Introduction to Computational Chemistry; Wiley & Sons: Chicester, UK, 1999. [33] Allinger, N. L.; Zhou, X.; Bergsma, J. J. Mol. Struc. (THEOCHEM) 1994, 312, 69–83. [34] van Duijnen, P. T.; Grozema, F. C.; Swart, M. J. Mol. Struc. (THEOCHEM) 1999, 464, 191–198.

Chapter 4

Multicomponent Synthesis of NHC complexes

Robin S. Bon,a Sander Jansen,a Rob F. Schmitz,a Frans J.J. de Kanter,a Andreas W. Ehlers,a Martin Lutz,b Anthony L. Spek,b Mareike C.

Jahnke,c F. Ekkehardt Hahn,c Marinus B. Groen,a Romano V.A. Orrua



cInstitut für Anorganische und Analytische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstrasse 36, D-48149 Münster, Germany

Abstract: N-heterocyclic carbenes (NHCs) are valuable ligands in transition metal catalysis, due to their unique electronic properties. However, only few routes towards unsymmetrically substituted imidazolidin-2-ylidenes are known. We have applied the multicomponent synthesis of 2H-2-imidazolines to access NHC complexes of rhodium, iridium and sulfur under mild conditions at room temperature. With this method a wide range of densely substituted NHC ligands can be synthesised. Electronic properties of the NHC complexes have been studied with 13C NMR spectroscopy, X-ray crystallography and IR spectroscopy.

Chapter 4

64

4.1 Introduction

The unique properties of N-heterocyclic carbenes (NHCs) stimulate their ongoing development as valuable ligands in coordination chemistry and homogeneous catalysis. The strong nucleophilic character and little π back-donating ability make these remarkably stable carbenes comparable to P-, N- or O-donating ligands rather than to classical Fischer- or Schrock-type carbenes.1 In fact, some NHCs serve as better σ donors than the best donating phosphane ligands, while the back-donation of metal electrons competes with π donation to the empty orbital by the nitrogen atoms. Electron rich organophosphane ligands have often been advantageously replaced by NHCs in transition metal (TM) catalysis.2 Important advantages of NHC ligands are their low sensitivity to air and moisture compared to their phosphane counterparts and their remarkable resistance to oxidation.3 In addition to beneficial electronic properties, the availability of established synthetic procedures gives access to NHCs bearing additional functional groups, leading to, for example, chiral ligands,4 bidentate and pincer ligands,2f easily recoverable catalysts,5 water soluble catalysts,6 and catalysts containing ‘flexible steric bulk’.7

In this Chapter, the history, structure, reactivity and electronic properties of NHCs are

summarised and established approaches to access them are discussed. After this our efforts in this area are described. Application of the multicomponent synthesis of imidazolines discussed in Chapters 2 and 3 forms the basis for mild and easy protocols to arrive at a range of diversely substituted NHC complexes. The merits of our synthetic methodology will be discussed in detail.

4.2 History of NHCs

NHCs derived from five-membered heterocycles represent the most common class of these molecules (Chart 1, A–J), but some four-8 six-9 and seven-membered10 analogues have also been reported (K–M). However, the most frequently used NHCs are imidazolin-2-ylidenes (A), imidazolidin-2-ylidenes (B), and benzimidazolin-2-ylidenes (C).

Chart 1

N NN N N N

N N N N

NN N

NNN N

NN

PN N

N

N N

NN

NN S N O

A B C D E F G

H I J K L M


65

In the early 1960’s, Wanzlick discovered that the stability of carbenes can be dramatically enhanced by the presence of amino groups next to the carbene carbon.11 He tried to prepare carbenes of type B by thermal elimination of CHCl3 from 2-(trichloromethyl)imidazolidine 1. Instead of the free carbene 2, the Wanzlick dimer 3 was isolated (Scheme 1). Attempts to prove the existence of an equilibrium between carbenes of type B and their Wanzlick dimers using cross-coupling experiments failed. However, the electron rich double bond of these enetetramines can be cleaved in reactions with electrophiles.12 Thus, the synthesis of transition metal complexes of NHCs of type A was first reported by Wanzlick and Schönherr13 and by Öfele in 1968.14 Lappert et al. synthesised complexes of NHCs of type B via the cleavage of enetetramines with transition metals,15 and they synthesised and characterised about 500 such complexes between 1971 and 1985.16 However, it was the isolation of the first stable free NHC of type A (4, Scheme 2) by Arduengo that triggered an explosive growth of interest in carbenes as ligands in organometallic complexes.17 The first stable derivative of B (5) was reported in 1995, again by Arduengo et al.18 The stability of free NHCs of type B is highly dependent on the steric effects of the nitrogen substituents.19 Carbenes of type C have an intermediate stability between A and B and the first analogue 6 was reported in 1999 by the group of Hahn.20

Scheme 1

N

N

P h

P h

1

CCl3N

N

P h

P h

3

N

NPh

PhN

N

Ph

Ph

2

22Δ Δ

X- CHCl3- CHCl3

Scheme 2

N

N

N

N

N

N

4 5 6

In the late 1990s, the first NHC complexes with high catalytic activities were patented,21 which gave the NHC research another impulse. For example, in Ru metathesis catalysts (Grubbs’ catalyst) and Pd cross coupling catalysts, PR3 ligands are replaced by NHCs. This resulted in more stable and highly active catalysts that were further developed for olefin metathesis,2e Pd catalysed C–C couplings2a,2d and hydrosilylation.2a

Chapter 4

66

4.3 Structure and Reactivity of NHCs

Carbenes are neutral compounds featuring a divalent carbon atom. The degree of hybridisation is dependent on the angle of the carbene substituents. A linear geometry implies an sp-hybridised carbene centre with two nonbonding degenerate orbitals (px and py). Bending the molecule breaks this degeneracy and causes the carbene carbon to adopt an sp2-type hybridisation, leaving the py orbital almost unchanged, while the px orbital acquires some s character (therefore it is usually called σ) (Figure 1). Since most carbenes are bent, their frontier orbitals will be systematically called σ and pπ.23

Figure 1. Relationship between the carbene bond angle and the nature of the frontier orbitals.

The carbene centre of NHCs has a singlet electronic ground state in which the paired electrons occupy an in plane σ orbital, leaving a p orbital vacant. The inductive effect of the nitrogen atoms induces a large σ–pπ gap by stabilising the nonbonding σ orbital while leaving the pπ orbital energetically unchanged. Additional mesomeric stabilisation of the carbene by the lone pairs at the N-substituents results in a formal three-centre four-electron π system. Hence, a combination of inductive (σ acceptor) and mesomeric (π donor) effects preserves the electron neutrality of the carbene centre by an electronic push-pull mechanism. The electronic properties can be described with the resonance structures in Figure 2.22

Figure 2. Resonance structures of free NHCs.

The bond lengths and bond angles account for the contribution of the carbene resonance structure 7. The N–C–N bond angles of the carbenes are smaller than those of their imidazol(in)ium salt precursors, where π donation has a larger contribution. They vary in the range 100–110°. The N–C bond distances are longer than those of their protonated precursors and vary in the range of 1.32–1.37 Å. These data are in good agreement with those expected for singlet carbenes, but also indicate some double bond character of the N–C bond. The carbene bond angles of imidazolidin-2-ylidenes B as well as their N–C bond distances are slightly larger than those of their unsaturated analogues A.24


67

Singlet carbenes are expected to have both nucleophilic and electrophilic properties, because of the lone pair in the σ orbital and the vacant pπ orbital. However, the reactivity of NHCs is mainly depending on the carbene lone pair that makes them very strong Lewis and Brønstedt bases. Some pKa values of (benz)imidazolium salts were measured and illustrate this strong basicity of NHCs (Table 1).25 In DMSO, 1,3-diisopropyl-4,5-dimethylimidazolium cation 9c has a pKa of 24 (entry 3).26 The measured pKa of the 1,3-di-tert-butylimidazolium cation 9b in DMSO is 22.7 (entry 2), which is significantly higher than the one measured in THF (20.0, entry 3), probably because of hydrogen bonding between the salt of 9b and DMSO.27 In water, pKa’s were derived from data from deuterium exchange reactions. Values around 23 were found for the 1,3-dimethylimidazolium cation 9a (entry 1).28 Two derivatives of carbene C, 1,3-bis-(methyl)benzimidazolyl-2-ylidene 11a and 1,3-bis-(phenyl) benzimidazolyl-2-ylidene 11b were found to be slightly less basic (entries 5 and 6).

Table 1. Measured pKa’s of (benz)imidazolium salts

entry azolium salt carbene R R’ solvent pKa

1 9a 10a Me H H2O 23.0 2 9b 10b tBu H DMSO 22.7 3 9b 10b tBu H THF 20.0 4 9c 10c iPr Me DMSO 24 5 11a 12a Me H2O 21.6 6 11b 12b Ph H2O 21.2

The influence of both nitrogen and carbon substituents on the pKa of NHCs has been

calculated.29 Aromatic side groups on nitrogen reduce the pKa with approximately 6 units. This can be explained by the strong inductive effect of aromatic rings on the nitrogen lone pair. However, when coplanarity of the aromatic substituent with the π system of the NHC is prevented (for example by the ortho-methyl groups of mesityl substituents), this effect is less pronounced. In carbenes of type A, groups on C–4 and C–5 also influence the pKa value. Electron withdrawing groups like chlorine dramatically decrease the basicity, while electron-donating methyl groups increase basicity. Measured pKa values of carbenes of type B were not found in the literature, probably because these species are too reactive. Calculations of pKa values of NHCs predict a higher basicity for saturated NHCs of about 1.5 pKa units. In the past, this was explained by the extra π stabilization of the nitrogens to the carbene, but there are also indications that the increased N–C–N bond angle is

Chapter 4

68

responsible for this difference in basicity.29 This would mean that the nitrogen lone pairs contribute to the basic character of NHCs.

Dimerisation of carbenes is one of the main decomposition pathways of NHCs and can be

seen as an indication of their stability and reactivity. In the Carter and Goddard formulation,30 the strength of the C=C double bond resulting from the dimerisation of singlet carbenes should correspond to that of a canonical C=C double bond (like the ethene double bond: 172 kcal mol−1) minus twice the singlet-triplet energy gap for the carbene. The singlet-triplet gap for carbenes of type A has been calculated to be ca. 85 kcal mol−1, giving a C=C bond strength of only (172−2×85) 2 kcal mol−1 for their dimers A=A. This weak bond strength does not compensate for the unfavourable entropy of dimerisation. Hence, dimerisation does not take place at room temperature (Scheme 3).31

Scheme 3

The singlet-triplet gap is smaller for carbenes of type B (~70 kcal mol−1), probably due to the saturation of the N-heterocyclic ring (no aromatic system to break). The Wanzlick dimer is readily formed and difficult to dissociate into carbenes (scheme 3).32 The only way to prevent dimerisation of the free carbene is to use sterically demanding N-substituents. According to recent studies, only one sterically demanding N-substituent is sufficient.19 For a long time, there has been controversy about the existence of an equilibrium between derivatives of B and their corresponding dimers B=B. Denk et al. succeeded in exchanging NHC units of a mixture of enetetramines at elevated temperature,19b but this cannot be regarded as proof for the existence of the Wanzlick equilibrium, because the exchange of NHC units can also be explained as a cycloaddition-cycloreversion. Both theoretical and experimental studies have proven that a protic catalyst (i.e. NH+) is required for the


69

dimerisation of carbenes of type N, (B may be regarded as a cyclic analogue of N) (Scheme 4).12,33

Scheme 4

Benzimidazolin-2-ylidenes C have an intermediate singlet–triplet energy gap. The formation and dissociation of the dimer C=C is primarily determined by the steric bulk of the nitrogen substituents (Scheme 3). This behavior emphasises the unusual properties of carbenes of type C, which have the topology of unsaturated NHCs A but show the reactivity of saturated derivatives B.34

Chart 2

Carbenes are relatively stable under oxidative conditions. For example, NHCs 13 and 17 are not only inert towards oxygen but are also unreactive towards other oxidising agents, like CuO, Cu2O and HgO.35 Clean oxidation to their corresponding urea derivatives 14 and 18 was observed with NO though.36 The ‘air sensitivity’ of carbenes like 13 and 17 is mainly due to attack of water, leading to ring opening to give the formamides 15 and 19. Depending on the nitrogen substituents, hydrolysis of carbenes of type A is rather slow at room temperature, while carbenes of type B are hydrolysed instantly. Because hydrolysis of 13 is not accelerated under acidic or basic conditions, it is unlikely that protonation of the carbene or nucleophilic attack of OH– are rate determining steps of the hydrolysis.

Chapter 4

70

Furthermore, many imidazolinium salts BH+ are relatively stable towards water. Most likely, the hydrolysis of NHCs proceeds via a direct insertion of the carbene into the O–H bond of water.35a Hydrogenation energies obtained from DFT calculations indicate that the insertion of carbenes 13 and 17 into H2 should be exothermic. In the absence of catalyst, both are inert towards hydrogen, but addition of catalytic amounts of Pd or Pt leads to slow hydrogen uptake and to clean formation of aminals 16 and 20.35a

Although most NHCs are used as ligands or as organocatalysts, it is noteworthy that they

can also be used as reagents.37 NHCs of types A, B and F have been used in various reactions with electron deficient olefins and acetylenes, aldehydes, and isocyanates. Even some multicomponent reactions with NHCs as inputs have been reported.38

4.4 The Nature of the Metal-NHC bond

Metal-NHC bonds are comparable with metal-phosphine bonds.39 Both phosphines and NHC ligands are soft nucleophiles and strong σ donors, though NHC ligands are slightly more nucleophilic and softer. This is supported by theoretical DFT calculations at Cr(CO)5L (L = NHC, PR3 or :C(NR2)2) complexes. CO replacement by NHCs is energetically favourable, while for phosphines CO exchange is unfavourable.1 In general, bulky nitrogen substituents lower the metal-NHC bond strength.40

In most cases, the M–Ccarbene bond of metal-NHC complexes is considered a single bond

in which the carbene donates its filled σ orbital, while π back-bonding is almost non-existent. The M– Ccarbene bond is strongly polarised although the net charge on the carbene carbon is negligible. The successful synthesis of main group metal NHC complexes, such as beryllium tris(1,3-dimethylimidazolin-2-ylidene)chloride, is regarded as empirical evidence for this bonding model,41 because main group elements are incapable of back-donating electrons into the carbene pπ orbital. However, it is noteworthy that NHC complexes of main group elements are often air and moisture sensitive, probably because no π electrons are available for back-bonding.41 NHC complexes containing transition metals generally exhibit much higher stabilities.

The assumption that NHCs are pure σ donors and that π back-bonding is negligible has

generally been based on the ‘single-bond’ character of the M–Ccarbene interactions deduced from crystallographically determined bond distances. Meyer stated: ‘While it is customary, and often instructive, to correlate a given bond length with the bond order in certain classes of compounds, such correlation is purely empirical and by itself is not sufficient to corroborate the nature of any metal-ligand interaction.42a Comparison of structural parameters of the imidazole rings in a series of isostructural NHC complexes containing electron rich, less electron rich and electron poor metal centres has provided evidence for


71

non-negligible metal-NHC π back-bonding. Increased M–Ccarbene π back-bonding in NHC complexes of electron rich metals causes decreased N–Ccarbene π back-bonding, reflected by the longer N–Ccarbene bond distances.

Several theoretical calculations claim to have also proven π back-bonding in the M–

Ccarbene bond.42 Meyer et al calculated the orbital diagram of the tripodal polycarbene 1,1,1-tris[(3-methylimidazolin-2-ylidene)-methyl]ethane in complex with copper. In molecular orbital analysis it was shown that the overlap of filled Cu 3d orbitals and empty NHC π orbitals is not negligible. Furthermore, energy decomposition analysis (EDA) of closely related Pd complexes allowed a quantitative comparison of π and σ contributions. It was found that the π back-bonding interactions contribute to approximately 15–30% of the complexes’ overall orbital interaction energy.42a EDA of Group 11 metal complexes of NHCs by Frenking et al. shows π interactions that are small but certainly not negligible compared to the σ interactions, while charge decomposition analysis (CDA) of these complexes reveals a significantly higher donation/back-donation ratio than in typical Fischer complexes.42b Lammertsma et al. found that for Cp(NHC)Ir=E complexes (E = CH2, NH, or PH), σ donation accounts for ~80% of the total orbital interaction.42c

Next to NHC-metal σ donation and metal-NHC π back-donation, another type of orbital

interaction has been studied. Molecular orbital analysis of highly electron deficient [Ir(NHC)2]PF6 complexes shows remarkable donation of electron density from the filled π orbital of NHCs to the empty d orbitals of the Ir atom, causing the unusual stability of the 14e complex.40 This kind of stabilisation of low-valent transition metal complexes might have important implications in catalysis, since these species are often the reactive intermediate in transition metal catalysis. Indeed, late TM-NHC compounds often display higher thermal stability compared to analogous phosphine systems.

From all these findings it can be concluded that the amount of π back-donation in TM-

NHC complexes is, in general, relatively small, but that it is highly dependent on the nature of the metal and its ligands.

Another feature that plays a role in the NHC–M binding is the recently described N٠٠٠M

coupling (Figure 3). The M٠٠٠N distance in Cr complexes is dramatically decreased in highly Lewis basic acyclic diaminocarbenes. Saturated carbenes also show somewhat shorter M٠٠٠N bond distances compared to unsaturated ones.1,43 It has been proposed that the nitrogen lone pairs interact with the metal centre of the complex. This phenomenon is likely responsible for the slightly larger Lewis basicity of saturated NHCs compared to the unsaturated NHCs, since they have larger N–C–N bond angles.

Chapter 4

72

L1 = 3.0 Å L2 = 2.9 Å N N

[M]

N N

[M]

R R R R N N

[M]

iPr iPr

iP r iPr

L1 L2 L3

[M] = Cr(CO)5

L3 = 2.2 Å

Figure 3. M٠٠٠N coupling in carbenes of type A, carbenes of type B, and in di-(N,N-diisopropylamino)-carbene. Values of L1 and L2 are average values from systems containing different R groups.

Although NHCs are generally regarded as excellent spectator ligands, they are not totally inert. Decomposition pathways of metal-NHC complexes include reductive elimination of the carbenes and cis ligands, decomplexation, displacement of the NHC by competing ligands, C–H or C–C activation of the nitrogen substituents and oxidative additions of the metal into C–H bonds.44 For example, C–H activation of the methyl substituents of the commonly employed mesityl side group can occur at modest temperatures. As this reaction is often reversible, it may not be observed, but as it generates transient metal hydrides, it may affect catalytic activity of the complex. In the presence of olefins, hydrogen transfer may occur making this reaction irreversible.

4.5 Synthetic Approaches

The most straightforward procedure to synthesise carbenes of type A and B is by deprotonation of the corresponding imidazol(in)ium salts (Scheme 5). Commonly employed bases are NaH, KH, LDA, KHMDS and even KOtBu. This last fact is surprising, because the pKa of t-butanol is several units lower than that of imidazol(in)ium salts. Deprotonation of these salts is likely driven by the precipitation of halide salts or the formation of NHC complexes when carried out in the presence of metals.

Scheme 5

The imidazolium salts AH+X− are accessible via two complementary synthetic routes: I) nucleophilic substitution (quarternisation of nitrogen) starting from the potassium salt of imidazole,45 and II) a multi-component reaction building up the heterocycle with the appropriate substituents in one step (Scheme 6).46 Usually procedure I is successful when using primary substituted alkyl halides, while higher substituted alkyl halides can lead to elimination by-products. Procedure II works well with a variety of nitrogen side groups, but the use of anilines (R is an aromatic side group) usually leads to highly coloured by-


73

products that are difficult to separate from the product.45 To avoid this, a two-step condensation is used to obtain N-aryl substituted imidazolium salts (Scheme 7, top).

Scheme 6

Scheme 7

Imidazolinium salts BH+X− can be obtained by condensation of 1,2-diamines with triethyl orthoformate. A quick way to generate symmetrically substituted 1,2-diamines is via reduction of 1,2-diimines (route IVa) or via amination of 1,2-dibromides (route IVb) (Scheme 7).45,47

Scheme 8

Carbenes of type C can be prepared by the reaction of an ortho-aminoaniline with thiophosgene to form a cyclic thiourea analogue (procedure V, Scheme 8). After reduction with potassium metal, the carbene is formed.20 This reductive method is derived from an

Chapter 4

74

early synthetic route proposed in 1993 and works well for simple achiral benzimidazolin-2-ylidenes.48 Procedure VI is an alternative method that produces benzimidazolium salts CH+X−. Two subsequent Buchwald-Hartwig aminations of 1,2-dibromobenzene give access to nitrogen substituted ortho-aminoanilines. Then, the benzimidazolium salt is formed using a condensation similar to procedure IV. This procedure allows the introduction of two different nitrogen substituents. Furthermore, this method enables the formation of products with chiral, non-racemic nitrogen side groups.49

Scheme 9

Methods I–VI are appropriate for the synthesis of simple (benz)imidazol(in)ium salts with a wide variety of nitrogen substituents. Variation of the C–4 and C–5 side groups of carbenes of type B can be achieved by using available 1,2-diamines 21 or by alkylation of imidazolines containing various R1–R5 groups 23 (Scheme 9). However, methods for the synthesis of NHCs containing distinct side groups in the carbon backbone are limited. In fact, the only general procedure has been described by the group of Hahn (Scheme 10).19c In this one-pot synthesis, a secondary amine 24 is deprotonated with n-BuLi. The secondary lithium amide is treated with CS2, followed by lithiation of the methyl group with s-BuLi. The dilithiated dithiocarbamate 26 is then allowed to react with an imine 27 to yield imidazolidin-2-thione 28. Cyclic thiourea derivatives like 28 can be reduced using Na/K alloy.

Scheme 10a

a Reagents and conditions: (a) 1) n-BuLi, THF, 0 ºC to rt, 30 min. 2) CS2, 0 ºC, 30 min; (b) s-BuLi, −78 ºC to −25 ºC, 4 h; (c)

27, −78 ºC to −10 ºC, 2 h; (d) K or Na/K, THF, reflux, 4 h.

Although NHC complexes of almost all metals of the periodic table are known, access to these compounds is mainly based on one general concept: the deprotonation of an


75

imidazoli(in)um salt and: i) complexation of the free carbene with a coordinatively unsaturated metal (complex) or ii) replacement of one or more ligands of a metal complex by the free carbene (Scheme 11). The cleavage of electron rich olefins was one of the early synthetic approaches towards metal-NHC complexes, but is rarely used nowadays. The complexation of the free isolated carbene is straightforward and very convenient when the NHC is sufficiently stable. NHCs can replace other ligands like phosphines, amines, ethers, carbonyls and halides, and even ηn bound ligands such as ethylene, cyclooctadiene and cyclopentadienyl anions. Cleavage of dimeric metal complexes is also possible.46 The thermodynamics of the exchange of phosphine ligands can be controlled by the nature of the NHC and phosphine ligands.55 In several cases, where more phosphines are present at the metal precursor, only one phosphine is replaced by an NHC ligand. This feature is controlled by the steric demand of both types of ligands and has played an important role in the synthesis of palladium and ruthenium catalysts that contain both types of ligands.56,57

Scheme 11

The in situ deprotonation of imidazol(in)ium salts is more suitable when NHCs are too labile in the free form, or when deprotonation requires milder conditions. Using an external base to deprotonate the imidazolium salts is usually a convenient method, but in some cases this can lead to more than one product. This happens, for example, with methylene bridged diimidazolium salts, because strong bases can deprotonate at the methylene bridge. Deprotonation by metal salts containing basic ligands is possible with very weak bases. This procedure can be carried out with metal-acetate complexes to give metal-NHC complexes and release of acetic acid. This is a general method to synthesise palladium and nickel complexes like 35 (Scheme 12). For rhodium and iridium, alkoxy ligands take over the role of the basic anion.46

Scheme 12

In case strong basic conditions cannot be used and in situ deprotonation by basic ligands is impossible, the use of carbene transfer reagents can be an alternative. Silver(I)oxide readily reacts with imidazol(in)ium salts to provide the silver carbene complexes50 that can easily transfer their carbene ligand to late transition metals (Chart 3).51

Chapter 4

76

Chart 3

Oxidative addition is an alternative method that has been adapted to the synthesis of palladium catalysts recently. Both calculations and experiments have shown that oxidative addition of imidazolium salts to group 10 metals is in some cases exothermal. 2-halo-imidazol(in)ium salts are more reactive than 2H-imidazol(in)ium salts, and nickel and platinum complexes are more reactive towards oxidative addition than palladium complexes. Small, electron rich ligands also facilitate oxidative addition.52 In a procedure recently described by Fürstner et al., 2-chloro-imidazolinium salt 40 adds to a palladium phosphine complex to form the corresponding Pd-NHC complex 41 (Scheme 13). The 2-chloro-imidazolinium salts 40 can be easily prepared by treatment of a cyclic thiourea 39 with oxalyl chloride.53 The synthesis of palladium hydride complexes by oxidative addition of 2H-imidazolium salts only proved possible with coordinately unsaturated group 10 metal complexes containing strong Lewis basic ligands, such as other NHCs.54

Scheme 13

4.6 Multicomponent Synthesis of NHC Precursors

As already mentioned, only few NHCs with dissimilar C–4 and C–5 substituents are known and only one general route towards such carbenes has been reported (Scheme 10). Although this procedure gives access to a range of unsymmetrically substituted imidazolidin-2-ylidenes 29, the harsh reaction conditions are only compatible with non-functionalised alkyl substituents. Recently, we reported a versatile multicomponent synthesis of 2H-2-imidazolines 45 (see also Chapters 2 and 3).58 The mild reaction conditions render this MCR compatible with a broad spectrum of aliphatic, aromatic, heteroaromatic and olefinic substituents and even with more delicate functional groups such as amines, alcohols, esters and primary chlorides. Because the substituents on C–4 and C–5 of the resulting 2H-2-imidazolines can be varied independently, we envisioned our MCR as a valuable tool for the synthesis of unprecedented types of NHCs 47 and their transition metal complexes 48 (Scheme 14).


77

Scheme 14

For the synthesis of a diverse set of NHC precursors 46, three amines, three aldehydes, three isocyanides and three halides were chosen (Chart 4). The multicomponent synthesis of known 2-imidazolines 64, 68 and 70 and the two new 2-imidazolines 61 and 66 was performed following established procedures (Table 2). Imidazoline 61 was made because it is known that NHCs are stabilised by bulky N-substituents. Several research groups have studied NHCs and NHC complexes containing (remote) ferrocenyl substituents at the nitrogens.59 Recently, even the generation of a metallocene-fused imidazol-2-ylidene and its mercury complex was reported.60 The elegant application of NHCs with redox-active ferrocenyl groups in an easily recyclable olefin metathesis catalyst has been described by Plenio.5 However, to the best of our knowledge, no NHCs with ferrocenyl substituents in the carbon backbone are known. Application of ferrocene carboxaldehyde 54 as the aldehyde component in our MCR gives easy access to 4-ferrocenyl substituted 2-imidazoline 66 (entry 4).

Chart 4

Chapter 4

78

Table 2. Synthesis of imidazol(in)ium salts entry amine aldehyde isocyanide imidazol(in)e yielda halide salt yielda

1 49 52 55 N

N

61

89%b 58 N

N

I−

62

98%c

2 49 52 55 N

N

61

89%b 60 N

N

Cl−

Me s

63

84%d

3 50 53 55 N

N

64

PMB

91%e 59 N

N

Br−

Ph

65

PMB

93%d

4 50 54 55 N

NPMBFc

6669%f 58 N

NPMBFc

I−

67

99%c

5 49 52 56 N

N

68Ph

MeO2C

86%g 58 N

N

69

I−PhMeO 2C

93%c

6 51 53 57 N

N

PNP70

39%e 58 N

N

PNP

71

I−

86%c

7 51 53 57 N

N

PNP72

27%e 58 N

N

P NP

73

I−

70%h

a Isolated yields are reported. b Conditions: Na2SO4, DCM, rt, 18 h. c Conditions: DCM, rt, 18 h. d Conditions: DMF, rt, 18 h. e See Chapter 3. f Conditions: MeOH, rt, 18 h. g See Chapter 2. h Conditions: 8 equiv. MeI, DCM, 100 ºC (microwave), 20 min. Mes = 2,4,6-trimethylphenyl; PMB = p-methoxybenzyl; Fc = ferrocenyl; PNP = p-nitrophenyl.

Alkylation of 2-imidazolines with alkyl or benzyl halides gives the imidazolinium halides

in high yields (entries 1–6). Although conversions are generally quantitative, small amounts


79

of the product are sometimes lost during washing of the salts with ether or pentane. Quarternisation with methyl iodide or benzyl bromide can be performed in DCM, but for the less reactive benzylic chlorides, more polar solvents like DMF are preferred (entry 2). In order to compare unsymmetrically substituted imidazolidin-2-ylidenes with their unsaturated analogues, we also decided to use imidazole 72, which is a side product of the synthesis of imidazoline 70, as carbene precursor. Methylation of imidazole 72 was successful using microwave heating and a large excess of methyl iodide (entry 7). The imidazol(in)ium salts were all isolated as stable but somewhat hygroscopic solids. 4.7 Synthesis of NHC Complexes

Deprotonation of imidazolinium iodide 62 was tested with either NaH or NaH/catalytic KOtBu (Scheme 15). However, deprotonation proved very slow and the resulting dark brown solids always contained mixtures of products that decomposed slowly upon storage as THF solution. NMR spectra showed the absence of the characteristic C-2 resonance for free imidazolidin-2-ylidenes like 74 around 240 ppm. Instead, the NMR spectra indicated that substantial amounts of NHC dimers 74=74 were present. Apparently, one t-butyl group is not sufficient to prevent dimerisation of carbenes of type B. Indeed, when deprotonation of 62 with NaH was followed by refluxing with [Rh(cod)Cl]2 in THF, a stable, crystalline NHC complex could be isolated in 52% yield. Replacement of the chloride on rhodium by the iodide that was present in 62 was confirmed by mass spectroscopy and X-ray crystallography (Figure 4). To ensure complete substitution of chloride by iodide, excess KI was added to the reaction mixture.

Scheme 15a

a Reagents and conditions: (a) NaH, THF, rt, 18 h; (b) NaH, KOtBu (cat.), THF, rt, 18 h; (c) 1) NaH, THF, rt, 18 h.

2) [Rh(cod)Cl]2, KI (xs), reflux, 20 h, 52%; (d) KOtBu, [Rh(cod)Cl]2, KI, rt, 18 h, 82%.

Although deprotonation of imidazolinium salts is usually faster with KOtBu than with NaH, t-butanol reacts with the resulting carbenes to form their corresponding alcohol adducts, which can be liberated again at elevated temperatures. Instead, a one-pot reaction between 62, KOtBu, KI and [Rh(cod)Cl]2 at room temperature results in deprotonation of 62 followed by trapping of the in situ generated NHC 74, giving rhodium complex 75 in 82% yield. Apparently, halogen exchange already takes place at room temperature.

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80

Both the two-step and the one-step method were used for the synthesis of several rhodium and iridium complexes (Table 3). All NHC complexes 75–78 were isolated as stable, crystalline solids. In general, the one-step deprotonation and complexation (method b in Table 3) gives higher yields (entries 1–6). The yield of Ir-NHC complex 78 could be enhanced by performing the reaction in refluxing THF (entry 8). Also at iridium, halogen exchange already takes place at room temperature.

Figure 4. Displacement ellipsoid plot of 75. Drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. Selected bond lengths [Å], angles [deg] and torsion angles [deg]: I1-Rh1 2.70624(17), Rh1-C1 2.0197(14), N1-C1 1.3481(18), N2-C1 1.3576(19); I1-Rh1-C1 86.10(4), Rh1-C1-N1 120.53(10), Rh1-C1-N2 131.58(10), N1-C1-N2 107.88(12); I1-Rh1-C1-N1 −85.36(11).

Table 3. Synthesis of Rh- and Ir-NHC complexesa

entry compound method yield entry compound method yield (ratio)b

1 75 a 52% 5 77 a 51% (89:11) 2 75 b 82% 6 77 b 63% (78:22) 3 76 a 55% 7 78 a 51% (52:48) 4 76 b 63% 8 78 b 49% (57:43)c a Reagents and conditions: (a) 1) NaH, THF, rt, 18 h. 2) [Rh(cod)Cl]2, KI (xs), reflux, 20 h; (b) KOtBu, [Rh(cod)Cl]2, KI,

rt, 18 h. b Isolated yields and ratios are reported. Ratios refer to relative amounts of rotamers. c This yield could be improved by performing the reaction in refluxing THF: 57% (67:33).


81

Figure 5. Displacement ellipsoid plot of 78a, the major, least polar isomer of 78. Drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. Selected bond lengths [Å], angles [deg] and torsion angles [deg]: Ir1-I1 2.67288(19), Ir1-C1 2.023(2), N1-C1 1.354(3), N2-C1 1.343(3); I1-Ir1-C1 90.11(6), Ir1-C1-N1 121.82(15), Ir1-C1-N2 129.67(16), N1-C1-N2 108.48(19); I1-Ir1-C1-N1 89.20(17).

Figure 6. Displacement ellipsoid plot of 78b, the minor, most polar isomer of 78. Drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. Selected bond lengths [Å], angles [deg] and torsion angles [deg]: Ir1-I1 2.6716(2), Ir1-C1 2.030(3), N1-C1 1.344(3), N2-C1 1.351(3); I1-Ir1-C1 92.09(7), Ir1-C1-N1 121.34(18), Ir1-C1-N2 129.94(19), N1-C1-N2 108.2(2); I1-Ir1-C1-N1 86.9(2).

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82

The NMR spectra of 77 and 78 show double sets of signals, which are caused by the formation of rotamers.61 Rotation of the carbene ligand around the TM-NHC axis is hindered for steric reasons. High temperature NMR experiments have shown that this rotation does not occur once the complex has formed.62 In case of iridium complex 78, the rotational isomers could be separated using flash column chromatography. Ultimate proof for the existence of the two rotational isomers was provided by X-ray crystal structure analysis of the two products. In the major, least polar fraction of 78, the carboxylic ester and the iodide are on opposite sides of the NHC plane (Figure 5), while in the minor, most polar fraction, they are on the same side (Figure 6).

Several methods exist to circumvent halogen exchange during the formation of TM-NHC

complexes. For example, an azolium salt containing a non-coordinating anion can be used as precursor.63 Imidazolinium hexafluorophosphate 79 can be obtained in nearly quantitative yield from reaction of imidazolinium iodide 69 with AgPF6 (Scheme 16). This reaction is driven by the precipitation of AgI from the DCM solution. Deprotonation of 79 and in situ complexation of the resulting carbene gave chloro complex 80 in high yield as a mixture of rotamers. When the same reaction sequence was applied to imidazolinium iodide 62, an inseparable mixture of chloro complex 82 and bis(carbene) complex Rh(cod)(NHC)2 · PF6 was isolated. Consequently, complex 82 was synthesised from imidazolinium tosylate 81, which was obtained in quantitative yield by alkylation of imidazoline 61 with methyl tosylate. In this case, the contaminating bis(carbene) complex, as its tosylate salt, can be easily removed by washing with water.

Scheme 16a

a Reagents and conditions: (a) AgPF6, DCM, rt, 30min; (b) KOtBu, [Rh(cod)Cl]2, Et4N+Cl−, THF, rt, 18 h; (c) MeOTs, DCM, rt,

18h; (d) KOtBu, [Rh(cod)Cl]2, LiCl, THF, rt, 18h.


83

Rhodium- (and iridium-) NHC complexes are being increasingly applied as catalysts for, amongst others, (asymmetric) hydrosilylations64 and cycloaddition reactions.65 Furthermore, an established method for determining the ligand properties of NHCs involves studying Rh-NHC complexes.64b,66 In order to compare our NHCs, we decided to synthesise a broader range of unsymmetrically substituted NHC complexes of rhodium (Table 4). Our one-step deprotonation/complexation procedure proved compatible with all imidazol(in)ium salts from Table 2 and provided complexes 83–87 in reasonable to high yields. Again, chiral NHCs gave rise to mixtures of rotamers (entries 2–4). The major isomers of 84 and 86 could be obtained as pure compounds easily by slow crystallisation. Complexes 84, 86 and 87 were studied using X-ray crystal structure analysis.

Table 4. Synthesis of Rh-NHC complexes entry imidazol(in)ium halide NHC complex yield (ratio)a

1 N

N

Cl−

Me s

63

N

NRh

Cl

83

Mes

54%

2 N

N

Br−

Ph

65

PMB

N

NPMB

RhI

84

Ph

81% (80:20)

3 N

NPMB

Fc

I−

67

N

NPMB

RhI

85

Fc

82% (58:42)

4 N

N

PNP

71

I−

N

NRhI

86

PNP

79% (82:18)

5 N

N

P NP

73

I−

N

NRhI

87

PNP

46%

a Isolated yields and ratios are reported. Ratios refer to relative amounts of rotamers.

Chapter 4

84

Figure 7. Displacement ellipsoid plot of two symmetry related molecules in the high temperature phase 84-I of the major isomer of 84 (200 K). Drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. Selected bond lengths [Å], angles [deg] and torsion angles [deg]: I1-Rh1 2.6748(3), Rh1-C1 2.023(3), N1-C1 1.351(3), N2-C1 1.342(3); I1-Rh1-C1 88.72(7), Rh1-C1-N1 125.12(18), Rh1-C1-N2 126.67(19), N1-C1-N2 108.2(2); I1-Rh1-C1-N1 85.5(2), N2-C3-C23-C24 −56.2(4), N2-C3-C23-C25 176.3(3), N2-C26-C27-C28 157.8(3), C29-C30-O1-C33 163.9(3). Symmetry operation i: 1-x, 1-y, 1-z.

Figure 8. Displacement ellipsoid plot of the two independent molecules in the low temperature phase 84-II of the major isomer of 84 (110 K). Drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. Selected bond lengths [Å], angles [deg] and torsion angles [deg]. Values for the second molecule are given in square brackets: I1-Rh1 2.6821(3) [2.6592(3)], Rh1-C11 2.020(3) [2.022(3)], N11-C11 1.346(4) [1.347(4)], N12-C11 1.337(4) [1.341(4)]; I1-Rh1-C11 89.01(9) [89.01(9)], Rh1-C11-N11 125.5(2) [124.1(2)], Rh1-C11-N12 126.8(2) [126.7(2)], N11-C11-N12 107.6(3) [109.0(3)]; I1-Rh1-C11-N11 84.4(3) [−88.2(3)], N12-C13-C123-C124 −53.8(4) [−71.7(4)], N12-C13-C123-C125 179.3(3) [168.5(3)], N12-C126-C127-C128 159.2(3) [−165.9(3)], C129-C130-O1-C133 168.5(3) [−176.3(3)].


85

Figure 9. Displacement ellipsoid plot of the major isomer of 86. Drawn at the 50% probability level. Hydrogen atoms and disordered solvent molecules are omitted for clarity. Selected bond lengths [Å], angles [deg] and torsion angles [deg]: I1-Rh1 2.68360(17), Rh1-C1 2.0183(15), N1-C1 1.3473(18), N2-C1 1.339(2); I1-Rh1-C1 88.86(4), Rh1-C1-N1 125.59(11), Rh1-C1-N2 125.78(10), N1-C1-N2 108.57(13); I1-Rh1-C1-N1 88.22(13).

Figure 10. Displacement ellipsoid plot of 87. Drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. Selected bond lengths [Å], angles [deg] and torsion angles [deg]: I1-Rh1 2.6652(2), Rh1-C1 2.028(2), N1-C1 1.348(3), N2-C1 1.360(3); I1-Rh1-C1 87.58(6), Rh1-C1-N1 128.43(15), Rh1-C1-N2 126.72(14), N1-C1-N2 104.84(17); I1-Rh1-C1-N1 90.56(18).

Chapter 4

86

Interestingly, crystals of the major isomer of complex 84 undergo a solid-solid phase transition upon cooling. The high temperature phase 84-I crystallises in the centrosymmetric space group P21/n with one independent molecule in the asymmetric unit (Figure 7). Close to the isopropyl group there is a small void. The low temperature phase 84-II crystallises in the non-centrosymmetric space group P21, which is a subgroup of P21/n (Figure 8). In the P21 phase there are two independent molecules in the asymmetric unit, which differ mainly in the conformation of the isopropyl group. Additionally, due to the phase transition, there are significant changes of intermolecular distances which make the packing motif of 84-II incompatible with P21/n. Over a wide temperature range (110 K–250 K) both phases are present. The different molecular structures show only slight variations in the bond lengths and angles around the carbene centre.

Table 5. Easy synthesis of imidazolidine-2-thionesa

entry imidazolinium halide imidazolidine-2-thione yieldb

1 N

N

I−

62

N

N

89

S

89%

2 N

N

Cl−

Mes

63

N

N

Mes

90

S

76%

3 N

N

Br −

Ph

65

PMB

N

N

Ph

91

PMB

S

89%

a Reagents and conditions: (a) KOtBu, S8, THF, rt, 2 h. b Isolated yields are reported.

As stated in Section 4.5, reduction of cyclic thioureas is a convenient method to produce

free NHCs in the absence of imidazolinium salts, thus preventing dimerisation (Scheme 10). Furthermore, imidazolidin-2-thiones have been applied for the synthesis of Pd-NHC complexes (Scheme 13) and guanidines.67 Although the synthesis of imidazolidine-2-thiones from imidazolinium salts is known, these reactions often involve the trapping of


87

preformed, free carbenes with elemental sulfur.59b,68 Instead, we used a modified procedure of Karkhanis et al. to perform one-pot reactions between imidazolinium halides of type 46, KOtBu and S8 at room temperature and isolated imidazolidine-2-thiones 89–91 in excellent yields (Table 5).69

4.8 Properties of the NHCs

The 13Ccarbene NMR chemical shifts (208–218 ppm) and Rh–Ccarbene coupling constants (43–47 Hz) of our saturated NHC transition metal complexes are in good agreement with values reported for complexes of other saturated NHCs (Table 6, entries 1–11).70,19c Furthermore, complex 87 shows a typical chemical shift (180.0 ppm) for Rh complexes of imidazolin-2-ylidenes A (entry 12).66,71 However, recent studies have shown that chemical shifts of carbene carbons and the coupling constants J(Rh–C) in 13C NMR, although usually specific for the type of carbon, do not show systematic order for an estimation of the σ donor strength.66

Table 6. 13C NMR chemical shifts δ of M(cod)X(NHC) complexes and Rh–Ccarbene coupling constants J of Rh(cod)X(NHC) complexesa

entry complex M X δ Ccarbene (ppm) J(Rh–Ccarbene) (Hz)

1 75 Rh I 213.3 43.5 2 76 Ir I 209.0 3 77b Rh I 213.3 43.8 4 78a Ir I 208.8 5 78b Ir I 209.2 6 80b Rh Cl 213.8 45.9 7 82 Rh Cl 214.0 45.6 8 83 Rh Cl 217.8 46.2 9 84b Rh I 217.8 45.6

10 85b Rh I 216.4 44.7 11 86b Rh I 213.7 44.5 12 87 Rh I 180.0 48.8

a Spectra were recorded in CDCl3. b Chemical shifts and coupling constants of main isomer are reported.

The X-ray crystal structures of the NHC complexes all show (slightly disturbed) square

planar coordination geometries, as expected for 16e Rh and Ir complexes. The different Rh complexes show only small differences in Rh–Ccarbene distances (Table 7, entries 1–5). However, the saturated NHC complexes show characteristic N1-C1-N2 angles around 108º (entries 1–4), which are 3–4º larger than that in complex 87 (entry 5), bearing an unsaturated NHC. To accommodate the steric requirements of t-butyl substituents in complexes 75, 78a and 78b, their M-C1-N2 angles are about 10º larger than their M-C1-N1 angles (entries 1, 6–7). When the two nitrogen substituents are sterically more alike, these

Chapter 4

88

angles are almost equal (entries 2–5). Furthermore, the plane of the five-membered carbene ring is almost perpendicular to the coordination plane of the complex (> 85º).

Table 7. Selected bond distances (Å), bond angles (deg) and torsion angles (deg) for M(cod)I(NHC) complexes

entry complex M M-C1 N1-C1-N2 M-C1-N1 M-C1-N2 I-M-C1-N1

1 75 Rh 2.0197(14) 107.88(12) 120.53(10) 131.58(10) −85.36(11) 2 84-I Rh 2.023(3) 108.2(2) 125.12(18) 126.67(19) 85.5(2) 3 84-IIa Rh 2.020(3) 107.6(3) 125.5(2) 126.8(2) 84.4(3) 2.022(3) 109.0(3) 124.1(2) 126.7(2) –88.2(3)

4 86 Rh 2.0183(15) 108.57(13) 125.59(11) 125.78(10) 88.22(13) 5 87 Rh 2.028(2) 104.84(17) 128.43(15) 126.72(14) 90.56(18) 6 78a Ir 2.023(2) 108.48(19) 121.82(15) 129.69(16) 89.20(17) 7 78b Ir 2.030(3) 108.2(2) 121.34(18) 129.94(19) 86.9(2) a Values of both molecules in the asymmetric unit are reported.

A direct method to estimate the σ donor strength of carbene ligands is determining the

pKa values of their corresponding acids, the azolium salts.26–28 However, a simple yet relatively precise method for the indirect measurement of the relative σ donating ability of NHCs involves the comparison of the IR data of complexes of the type Rh(CO)2X(NHC), which can be easily obtained from Rh(cod)X(NHC) complexes. A greater σ basicity of the NHC ligand is related to a lower stretching frequency of the CO’s.42a Although traditionally Rh(CO)2Cl(NHC) complexes were compared using this IR method, analysis of their iodo analogues is being increasingly reported.66

Scheme 17a

a Reagents and conditions: (a) CO, THF, rt, 10 min.

Rh(CO)2I(NHC) complexes 94–97 (Chart 5) are easily accessible by the quantitative exchange of the cod ligand of Rh(cod)I(NHC) complexes against two CO molecules (Scheme 17). In most cases, the resulting complexes are air-stable as solids, but they decompose quickly when exposed to air in solution.

The carbonyl stretching frequencies of complexes 94–97 were compared to those

reported for model systems 98–102 (Table 8). This comparison shows that the saturated carbenes in complexes 94–97 induce a higher electron density at the Rh centre than the parent NHC 99 of type B, N,N-dimethylimidazolidin-2-ylidene. In fact, the amount of σ


89

donation of the NHC in complexes 94–96 even approaches that in pyrazolin-3-ylidene complex 98. However, it must be noted that for a more precise comparison of the carbonyl stretching frequencies, medium effects, which can cause small deviations (compare entries 2 and 3), should be excluded by performing all IR measurements in the same medium. Unfortunately, insufficient material is currently available.

Chart 5

Table 8. Carbonyl stretching frequencies ν of Rh(CO)2I(NHC) complexes

entry complex medium ν(CO)

sym. (cm−1) ν(CO)

asym. (cm−1) ν(CO)

average (cm−1) 1 94 KBr tablet 2069 1991 2030 2 95 KBr tablet 2067 1996 2032 3 95 film on NaCl 2065 1994 2030 4 96 film on NaCl 2067 1994 2031 5 97 film on NaCl 2070 1998 2034 6 98a DCM solution 2066 1993 2030 7 99a DCM solution 2072 1999 2036 8 100a DCM solution 2073 2000 2037 9 101a DCM solution 2075 2001 2038 10 102a DCM solution 2078 2006 2042 a Data were taken from reference 66.

4.9 Conclusions

We have successfully applied the multicomponent synthesis of 2H-2-imidazolines in the preparation of a range of unsymmetrically substituted imidazolidin-2-ylidene complexes under mild conditions. Substituents at N–1, N–3, C–4 and C–5 can be varied easily and independently by choosing the appropriate amine, aldehyde, isocyanide or halide in the two-step synthesis of the NHC precursors. Deprotonation of the imidazolium salts with

Chapter 4

90

KOtBu and direct complexation of the in situ generated NHCs at room temperature affords Rh- and Ir-NHC complexes or, if elemental sulfur is used as the trapping agent, imidazolidin-2-thiones. Existence and stability of two hindered rotamers of M(cod)X(NHC) complexes has been unambiguously proven by the separation and X-ray crystal structure determination of two rotamers of Ir complex 78. Also 4-(p-nitrophenyl)imidazoles, which are side products of reactions between amines, aldehydes and p-nitrobenzyl isocyanide 57, can be used in the synthesis of NHC complexes. Data obtained from NMR spectroscopic and X-ray crystallographic studies of the complexes correspond well with earlier reported properties of NHCs. Carbonyl stretching frequencies of the Rh(CO)2I(NHC) complexes that were obtained by ligand exchange indicate that the saturated NHC ligands exhibit σ donation comparable to pyrazolin-3-ylidene ligands, which makes them potential candidates for future application in transition metal catalysis.


Dr. Marek Smoluch (Vrije Universiteit Amsterdam) is gratefully acknowledged for conducting (HR)MS measurements. Elemental analyses have been measured at the Westfälischen Wilhelms-Universität Münster. This work was partially supported (M.L., A.L.S.) by the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (CW-NWO).


General Information: All reactions were carried out under an inert atmosphere of argon or dry nitrogen (glovebox). Standard syringe techniques were applied for transfer of air sensitive reagents and dry solvents. Melting points were measured using a Stuart Scientific SMP3 melting point apparatus and are uncorrected. Infrared (IR) spectra were obtained from CHCl3 films on NaCl tablets (unless noted otherwise), using a Matteson Instuments 6030 Galaxy Series FT-IR spectrophotometer and wavelengths (ν) are reported in cm−1. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 (400.13 MHz and 100.61 MHz respectively), a Bruker Avance 250 (250.13 MHz and 62.90 MHz respectively) or a Bruker Avance 200 (200.13 MHz and 50.32 MHz respectively) with chemical shifts (δ) reported in ppm downfield from tetramethylsilane. Peak assignment was also done with the aid of gs-COSY, gs-HMQC and gs-HMBC measurements. MS and HRMS spectra data were recorded on a Finnigan Mat 900 spectrometer. Chromatographic purification refers to flash chromatography using the indicated solvent (mixture) and Baker 7024-02 silica gel (40μ, 60 Å). Thin Layer Chromatography was performed using silica plates from Merck (Kieselgel 60 F254 on aluminium with fluorescence indicator. Compounds on TLC were visualised by UV-detection. THF and Et2O were dried and distilled from sodium benzophenone ketyl prior to use. DCM was dried and distilled from CaH2 prior to use. Petroleum ether (PE 40–65) was distilled prior to use. Isocyanides 55,58a 56,58a and 57,58b [Rh(cod)Cl]2

72 and [Ir(cod)Cl]273 were

prepared according to literature procedures. Other commercially available reagents were used as purchased. Microwave Experiments: Microwave-assisted reactions were performed in a Discover (CEM Corporation) single-mode microwave instrument producing controlled irradiation at 2450 MHz, using standard sealed microwave glass vials. Reaction temperatures were monitored with an IR sensor on the outside wall of the reaction vials. Reaction times refer to hold times at the indicated temperatures, not to total irradiation times.


91

General Procedure I for the Synthesis of 2-Imidazolines: Reactions were carried out at a concentration of 1 M of amine, 1 M of aldehyde and 0.5 M of isocyanide in dry DCM, unless noted otherwise. Na2SO4 and the aldehyde were added, at rt, to a stirred solution of the amine. After the mixture was stirred for 2 h, the isocyanide was added and the reaction mixture was stirred at rt for an additional 18 h. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (PE:EtOAc:Et3N = 2:1:0.01, gradient, unless stated otherwise).

2-Imidazoline 61. According to General Procedure I, reaction between tert-butylamine 49 (1.46 g, 20 mmol), p-formaldehyde 52 (600 mg, 20.0 mmol) and isocyanide 55 (2.0 g, 10.5 mmol), followed by flash column chromatography, afforded 61 (2.58 g, 89%) as a light yellow solid. Crystallisation from pentane/Et2O affords white crystals. Mp 95–96 ºC; 1H NMR (250 MHz, CDCl3): δ (ppm) 7.68 (d, J = 6.9 Hz, 2H), 7.50–7.32 (m, 7H), 3.73 (s, 2H), 1.42 (s, 9H); 13C NMR (63 MHz, CDCl3): δ (ppm) 155.6 (CH), 150.6 (2×C), 140.3 (2×C), 128.7 (2×CH), 128.4

(2×CH), 124.2 (2×CH), 120.1 (2×CH), 79.1 (C), 55.6 (CH2), 53.1 (C), 28.9 (3×CH3); IR (neat) 2973 (s), 1674 (m), 1585 (s), 1450 (s), 1236 (s); HRMS (EI, 70 eV) calculated for C19H20N2 (M+) 276.1626, found 276.1617; Elemental analysis: calculated for C19H20N2 (%): C 82.57, H 7.29, N 10.14, found C 82.42, H 7.44, N 10.06. General Procedure II for the Synthesis of 2-Imidazolinium salts: Reactions were carried out at a concentration of 0.15–0.25 M of imidazoline in dry DCM, unless noted otherwise. The halide was added to a stirred solution of the imidazoline and the reaction mixture was stirred at rt for 18 h. Then, the reaction mixture was concentrated in vacuo. The crude product was washed with pentane or Et2O.

2-Imidazolinium iodide 62. According to General Procedure II, alkylation of imidazoline 61 (1.99 g, 7.2 mmol) with methyl iodide 58 (1.08 g, 7.6 mmol) followed by washing with Et2O afforded salt 62 as a white solid (2.95 g, 98%). 1H NMR (250 MHz, CDCl3): δ (ppm) 7.75–7.70 (m, 4H), 7.57–7.43 (m, 4H), 4.26 (s, 2H), 2.91 (s, 3H), 1.69 (s, 9H); 13C NMR (50 MHz, CDCl3): δ (ppm) 157.2 (CH), 141.7 (2×C), 140.2 (2×C), 131.1 (2×CH), 129.4 (2×CH), 124.3 (2×CH), 120.7 (2×CH), 74.8 (C), 57.9 (C), 56.6 (CH2), 30.7 (CH3), 28.2 (3×CH3); IR (neat):

1633 (s), 1450 (m), 1307 (m), 1269 (m).

2-Imidazolinium iodide 63. According to General Procedure II, alkylation of imidazoline 61 (770 mg, 2.8 mmol) with 2,4,6-trimethylbenzyl chloride 60 (475 mg, 2.8 mmol) in DMF (15 mL), followed by washing with pentane, afforded 63 (1.04 g, 84%) as a white solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 10.44 (s, 1H), 7.60 (d, J = 7.5 Hz, 2H), 7.52 (d, J = 7.6 Hz, 2H), 7.45–7.38 (m, 2H), 7.28–7.23 (m, 2H), 6.45 (s, 2H), 4.78 (s, 2H), 4.23 (s, 2H), 2.09 (s, 3H), 1.92 (s, 6H), 1.67 (s, 9H); 13C NMR (63 MHz, CDCl3): δ (ppm) 158.6 (CH), 142.2 (2×C),

139.9 (2×C), 137.9 (C), 137.6 (2×C), 130.5 (2×CH), 129.1 (2×CH), 128.9 (2×CH), 126.3 (C), 124.0 (2×CH), 120.4 (2×CH), 74.5 (C), 58.0 (CH2), 57.8 (C), 44.6 (CH2), 28.3 (3×CH3), 20.7 (CH3), 19.7 (2×CH3); IR (neat): 1626 (s), 1450 (m), 1217 (m).

2-Imidazolinium bromide 65. According to General Procedure II, alkylation of imidazoline 64 (1.4 g, 3.7 mmol) with benzyl bromide 59 (751 mg, 4.4 mmol), followed by washing with cold Et2O, afforded 65 (1.9 g, 93%) as a white solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 10.50 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.56–7.35 (m, 5H), 7.29–7.20 (m, 1H), 7.18–6.97 (m, 7H), 6.90–6.87 (m, 2H), 5.37 (d, J = 14.4 Hz, 1H), 4.72 (d, J = 14.4 Hz, 1H), 4.32 (d, J = 5.3 Hz, 1H), 4.30 (d, J = 14.4 Hz, 1H) , 4.06 (d, J = 14.4 Hz, 1H), 3.86

(s, 3H), 2.19–2.13 (m, 1H), 0.77 (d, J = 6.9 Hz, 3H), 0.60 (d, J = 7.0 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 160.9 (CH), 160.1 (C), 143.1 (C), 141.5 (C), 140.1 (C), 137.9 (C), 133.2 (C), 131.0 (CH), 130.6 (CH), 130.4 (2×CH), 129.1 (2×CH), 129.0 (CH), 128.5 (2×CH), 128.4 (CH), 127.9 (CH), 127.4 (CH), 125.3 (CH), 124.6

N

N

N

N+

I −

N

N+

Cl−

Mes

N

NPMB

+Br−

Ph

Chapter 4

92

(C), 120.7 (CH), 120.2 (CH), 114.7 (2×CH), 79.2 (C), 74.2 (CH), 55.4 (CH3), 51.8 (CH2), 49.3 (CH2), 28.0 (CH), 19.3 (CH3), 18.6 (CH3); IR (neat): 1626 (s), 1514 (m), 1452 (m), 1252 (m).

2-Imidazoline 66. According to General Procedure I, reaction between p-methoxybenzylamine 50 (685 mg, 5.0 mmol), ferrocenecarboxaldehyde 54 (1.07 g, 5.0 mmol) and isocyanide 55 (500 mg, 2.6 mmol) in MeOH (15 mL), followed by flash column chromatography, afforded 66 (936 mg 69%) as an orange solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.67–7.63 (m, 1H), 7.54–7.31 (m, 7H), 7.23–7.17 (m, 1H), 7.11–6.96 (m, 4H), 4.98 (d, J = 14.5 Hz, 1H), 4.95 (s, 1H), 4.50 (d, J = 14.5 Hz, 1H), 4.14 (br s, 1H), 3.95 (br s, 1H), 3.92 (s, 3H), 3.90 (s, 5H), 3.77

(br s, 1H), 3.13 (d, J = 1.1 Hz, 1H); 13C NMR (63 MHz, CDCl3): δ (ppm) 159.3 (C), 159.1 (CH), 149.6 (C), 145.7 (C), 141.4 (C), 139.9 (C), 129.2 (2×CH), 129.1 (C), 128.5 (CH), 128.0 (CH), 127.7 (CH), 126.7 (CH), 126.0 (CH), 124.4 (CH), 119.5 (CH), 119.1 (CH), 114.5 (2×CH), 85.0 (C), 84.1 (C), 69.4 (CH), 66.5 (5×CH), 67.8 (CH), 66.9 (CH), 66.3 (CH), 65.1 (CH), 55.4 (CH3), 50.2 (CH2); IR (neat) 1599 (s), 1512 (s), 1448 (m), 1248 (s); HRMS (EI, 70 eV) calculated for C33H28FeN2O (M+) 524.1551, found 524.1533.

2-Imidazolinium iodide 67. According to General Procedure II, alkylation of imidazoline 66 (380 mg, 0.73 mmol) with methyl iodide 58 (109 mg, 0.77 mmol) followed by washing with pentane afforded salt 67 (481 mg, 99%) as a light brown solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 9.10 (s, 1H), 8.23–8.20 (m, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.68–7.37 (m, 6H), 7.20–7.09 (m, 1H), 7.06 (d, J = 8.6 Hz, 2H), 5.65 (s, 1H), 5.21 (d, J = 13.6 Hz, 1H), 5.17 (d, J = 13.8 Hz, 1H), 4.26–4.25 (m, 1H), 4.17–4.16 (m, 1H), 3.96–3.94 (m, 1H), 3.92 (s, 5H), 3.89 (s, 3H),

3.21–3.20 (m, 1H), 2.70 (s, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 160.2 (C), 159.3 (CH), 141.4 (C), 141.2 (C), 140.9 (C), 138.3 (C), 131.2 (CH), 131.0 (2×CH), 130.8 (CH), 129.5 (CH), 127.7 (CH), 126.5 (CH), 126.0 (CH), 125.4 (C), 120.4 (CH), 120.3 (CH), 114.9 (2×CH), 80.0 (C), 78.3 (C), 72.3 (CH), 69.2 (5×CH), 68.5 (CH), 68.2 (CH), 68.1 (CH), 66.0 (CH), 55.4 (CH3) 50.3 (CH2), 31.3 (CH3); IR (neat) 1639 (s), 1514 (m), 1250 (s).

2-Imidazolinium iodide 69. According to General Procedure II, alkylation of imidazoline 68 (1.28 g, 4.9 mmol) with methyl iodide 58 (734 mg, 5.17 mmol) followed by washing with pentane afforded salt 69 (1.8 g, 93%) as a white solid. 1H NMR (400 MHz, CDCl3): δ (ppm) 9.73 (s, 1H), 7.51–7.46 (m, 3H,), 7.37–7.36 (m, 2H), 4.80 (d, J = 12.2 Hz, 1H), 4.01 (s, 3H),

3.94 (d, J = 12.2 Hz, 1H), 3.43 (s, 3H), 1.58 (s, 9H); 13C NMR (101 MHz, CDCl3): δ (ppm) 168.9 (C), 156.6 (CH), 134.0 (C), 130.1 (CH), 129.8 (2×CH), 126.4 (2×CH), 75.9 (C), 58.1 (C), 57.7 (CH2), 54.1 (CH3), 33.8 (CH3), 28.1 (3×CH3); IR (neat) 2974 (s), 1743 (s), 1633 (s), 1265 (s), 1230 (s), 1196 (s).

2-Imidazolinium iodide 71. According to General Procedure II, alkylation of imidazoline 70 (500 mg, 1.8 mmol) with methyl iodide 58 (284 mg, 2.0 mmol) followed by washing with Et2O afforded salt 71 (656 mg, 86%) as a white solid. 1H NMR (250 MHz, DMSO-d6): δ (ppm) 8.77 (s, 1H), 8.34 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 5.34 (d, J = 4.6 Hz, 1H), 4.26–4.11 (m,

1H), 3.64–3.53 (m, 1H), 2.94 (s, 3H), 2.60–2.39 (m, 1H), 1.43 (d, J = 4.8 Hz, 3H), 1.27 (d, J = 4.7 Hz, 3H), 0.92 (d, J = 4.4 Hz, 6H); 13C NMR (63 MHz, DMSO-d6): δ (ppm) 156.3 (CH), 147.9 (C), 144.5 (C), 128.7 (2×CH), 124.4 (2×CH), 72.4 (CH), 63.4 (CH), 47.7 (CH), 32.6 (CH3), 27.4 (CH), 21.2 (CH3), 20.7 (CH3),16.7 (CH3),13.8 (CH3); IR (KBr) 1743 (s), 1633 (s), 1265 (m), 1230 (m), 1196 (m).

2-Imidazolium iodide 73. Methyl iodide 58 (988 mg, 7.0 mmol) was added to a solution of imidazole 72 (238 mg, 2.8 mmol) in DCM (4 mL) in a microwave vessel. The reaction mixture was heated in the microwave at 100 ºC for 20 min. After cooling, the reaction mixture was concentrated in vacuo. After washing with Et2O, salt 73 (253 mg, 70%) was isolated as a white solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 10.38 (s, 1H), 8.41 (d, J = 8.6 Hz, 2H), 7.80 (d, J =

8.6 Hz, 2H), 4.68–4.62 (m, 1H), 3.82 (s, 3H), 3.15–3.11 (m, 1H), 1.82 (d, J = 6.7 Hz, 6H), 1.22 (d, J = 7.1 Hz,

N

NPMBF c

N

NPMB

+I−

Fc

N

N+

I−PhMeO2C

N

N+

I −PNP

N

N+

I−PNP


93

6H); 13C NMR (63 MHz, CDCl3): δ (ppm) 149.2 (C), 136.5 (C), 135.7 (CH), 132.9 (2×CH), 132.4 (C), 128.3 (C), 124.2 (2×CH), 51.1 (CH), 35.2 (CH3), 24.7 (CH), 24.0 (2×CH3), 22.1 (2×CH3); IR (neat) 1522 (s), 1348 (s). General Procedure III for the Synthesis of M(cod)X(NHC) Complexes: In a glovebox, NaH (12 mg, 0.5 mmol) was added to a solution of imidazolinium halide (0.5 mmol) in THF (5–8 mL). After stirring the reaction mixture at rt for 18 h, the reaction mixture was filtered and the filtrate transferred to a Schlenk tube containing [Rh(cod)Cl]2 or [Ir(cod)Cl]2 (0.23–0.24 mmol). THF (10 mL) was added and the reaction mixture was stirred at reflux for 18 h. After cooling, the mixture was filtered through a pad of celite, concentrated in vacuo and purified using flash column chromatography (pentane:DCM = 4:1, gradient). General Procedure IV for the Synthesis of M(cod)X(NHC) Complexes: Reactions were carried out at a concentration of 0.04 M of imdazol(in)ium salt in dry THF. A Schlenk tube was charged with imidazol(in)ium salt (1 equiv.), KOtBu (1 equiv.), [Rh(cod)Cl]2 or [Ir(cod)Cl]2 (0.95 equiv.), and KI (3 equiv.). THF was added and the reaction mixture was stirred at rt for 18 h. Then, the mixture was filtered through a pad of celite, concentrated in vacuo and purified using flash column chromatography (pentane:DCM = 4:1, gradient).

Rh-NHC complex 75. Method A: According to General Procedure III, reaction between imidazolinium iodide 62 (209 mg, 0.5 mmol), NaH (12 mg, 0.5 mmol), [Rh(cod)Cl]2 (113 mg, 0.23 mmol) and KI (249 mg, 1.5 mmol), followed by flash column chromatography, afforded 75 (150 mg, 52%) as an orange/yellow solid. Method B: According to General Procedure IV, reaction between imidazolinium iodide 62 (209 mg, 0.5 mmol), KOtBu (56 mg, 0.5 mmol), [Rh(cod)Cl]2 (113 mg, 0.23 mmol) and KI (249 mg, 1.5 mmol), followed

by flash column chromatography, afforded 75 (238 mg, 82%) as an orange/yellow solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.86–7.83 (m, 1H), 7.71–7.66 (m, 2H), 7.47–7.23 (m, 5H), 5.22 (br s, 2H), 4.08 (d, J = 10.8 Hz, 1H), 3.96 (d, J = 10.8 Hz, 1H), 3.65 (br s, 2H), 3.19 (s, 3H), 2.37–2.21 (m, 3H), 2.15–2.07 (m, 2H), 1.90 (s, 9H), 1.82–1.73 (m, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 213.3 (d, J = 43.5 Hz, C), 145.7 (C), 145.1 (C), 140.5 (C), 139.4 (C), 129.5 (CH), 129.4 (CH), 129.0 (CH), 128.3 (CH), 125.0 (CH), 122.8 (CH), 120.3 (CH), 120.0 (CH), 95.2 (d, J = 6.9 Hz, CH), 93.5 (d, J = 6.7 Hz, CH), 74.2 (C), 74.0 (d, J = 15.4 Hz, CH), 70.4 (d, J = 14.0 Hz, CH), 59.7 (CH2), 56.6 (C), 35.3 (CH3), 33.9 (CH2), 30.9 (CH2), 30.2 (3×CH3), 30.2 (CH2), 27.9 (CH2); IR (neat) 1475 (s), 1433 (s); HRMS (EI, 70 eV) calculated for C28H34IN2Rh (M+) 628.0822, found 628.0820. Crystals suitable for X-ray crystal structure determination were obtained by the slow diffusion of pentane into a saturated solution of 75 in DCM. Mp 230–233 ºC.

Ir-NHC complex 76. Method A: According to General Procedure III, reaction between imidazolinium iodide 62 (209 mg, 0.5 mmol), NaH (12 mg, 0.5 mmol), [Ir(cod)Cl]2 (154 mg, 0.23 mmol) and KI (249 mg, 1.5 mmol), followed by flash column chromatography, afforded 76 (182 mg, 55%) as an orange solid. Method B: According to General Procedure IV, reaction between imidazolinium iodide 62 (209 mg, 0.5 mmol), KOtBu (56 mg, 0.5 mmol), [Ir(cod)Cl]2 (154 mg, 0.23 mmol) and KI (249 mg, 1.5 mmol), followed by flash

column chromatography, afforded 76 (209 mg, 63%) as an orange solid, which could be recrystallised by the slow diffusion of pentane into a saturated solution of the complex in DCM. Mp 236–238 ºC (decomp.); 1H NMR (250 MHz, CDCl3): δ (ppm) 7.88–7.85 (m, 1H), 7.72–7.67 (m, 2H), 7.49–7.29 (m, 5H), 4.83–4.72 (m, 2H), 4.13 (d, J = 10.9 Hz, 1H), 4.04 (d, J = 10.9 Hz, 1H), 3.25–3.13 (m, 2H), 3.02 (s, 3H), 2.34–2.24 (m, 1H), 2.18–1.84 (m, 4H), 1.81 (s, 9H), 1.56–1.29 (m, 3H); 13C NMR (101 MHz, CDCl3): δ (ppm) 209.0 (C), 145.7 (C), 145.1 (C), 140.5 (C), 139.6 (C), 129.53 (CH), 129.50 (CH), 129.0 (CH), 128.4 (CH), 124.8 (CH), 122.9 (CH), 120.9 (CH), 120.0 (CH), 80.5 (CH), 79.7 (CH), 74.4 (C), 60.1 (CH2), 56.94 (C), 56.93 (CH), 54.3 (CH), 35.0 (CH3), 34.4 (CH2), 31.5 (CH2), 30.8 (CH2), 30.6 (3×CH3), 28.6 (CH2); IR (neat) 1473 (s), 1448 (s), 1429 (s), 1304 (s); HRMS (EI, 70 eV) calculated for C28H34IIrN2 (M+) 718.1396, found 718.1370; Elemental analysis: calculated for C28H34IIrN2 (%): C 46.86, H 4.77, N 3.90, found C 46.62, H 4.78, N 3.87.

N

NRh

cod

I

N

NI r

cod

I

Chapter 4

94

Rh-NHC complex 77. Method A: According to General Procedure III, reaction between imidazolinium iodide 69 (201 mg, 0.5 mmol), NaH (12 mg, 0.5 mmol), [Rh(cod)Cl]2 (113 mg, 0.23 mmol) and KI (249 mg, 1.5 mmol), followed by flash column chromatography, afforded 77 (143 mg, 51%) as a 89:11 mixture of rotamers as an orange/yellow solid. Method B: According to General Procedure IV, reaction between imidazolinium iodide 69

(300 mg, 0.75 mmol), KOtBu (84 mg, 0.75 mmol), [Rh(cod)Cl]2 (176 mg, 0.35 mmol) and KI (374 mg, 2.25 mmol), followed by flash column chromatography, afforded 77 (271 mg, 63%) as a 78:22 mixture of rotamers as a yellow solid. Main isomer: 1H NMR (250 MHz, CDCl3): δ (ppm) 7.47–7.33 (m, 5H), 5.22–5.19 (m, 2H), 4.41 (d, J = 11.3 Hz, 1H), 3.92 (s, 3H), 3.78 (d, J = 11.3 Hz, 1H), 3.72–3.60 (m, 1H), 3.69 (s, 3H), 3.48–3.41 (m, 1H), 2.55–2.37 (m, 2H), 2.29–2.04 (m, 3H), 1.94–1.88 (m, 1H), 1.82 (s, 9H), 1.77–1.64 (m, 2H); 13C NMR (63 MHz, CDCl3): δ (ppm) 213.3 (d, J = 43.8 Hz, C), 171.7 (C), 137.8 (C), 129.1 (2×CH), 128.6 (CH), 126.7 (2×CH), 95.3 (d, J = 7.0 Hz, CH), 93.4 (d, J = 6.7 Hz, CH), 74.9 (C), 73.9 (d, J = 15.3 Hz, CH), 70.8 (d, J = 14.0 Hz, CH), 60.9 (CH2), 56.8 (C), 52.8 (CH3), 37.8 (CH3), 33.9 (CH2), 30.9 (CH2), 30.1 (3×CH3), 30.0 (CH2), 27.9 (CH2); IR (neat) 1739 (s), 1475 (m), 1433 (s), 1221 (s); HRMS (EI, 70 eV) calculated for C24H34IN2O2Rh (M+) 612.0720, found 612.0739; Elemental analysis: calculated for C24H34IN2O2Rh (%): C 47.07, H 5.60, N 4.57, found C 46.46, H 5.45, N 4.63.

Ir-NHC complex 78. Method A: According to General Procedure III, reaction between imidazolinium iodide 69 (201 mg, 0.5 mmol), NaH (12 mg, 0.5 mmol), [Ir(cod)Cl]2 (154 mg, 0.23 mmol) and KI (249 mg, 1.5 mmol), followed by flash column chromatography, afforded two rotamers of 78 (least polar fraction 78a: 88 mg, 27%; most polar fraction 78b: 81 mg, 25%) as orange solids. Method B: According to General Procedure IV, reaction

between imidazolinium iodide 69 (201 mg, 0.5 mmol), KOtBu (56 mg, 0.5 mmol), [Ir(cod)Cl]2 (154 mg, 0.23 mmol) and KI (249 mg, 1.5 mmol), followed by flash column chromatography, afforded two rotamers of 78 (least polar fraction 78a: 91 mg, 28%; most polar fraction 78b: 67 mg, 21%) as orange solids. Method C: According to General Procedure IV, reaction between imidazolinium iodide 69 (201 mg, 0.5 mmol), KOtBu (56 mg, 0.5 mmol), [Ir(cod)Cl]2 (154 mg, 0.23 mmol) and KI (249 mg, 1.5 mmol) in refluxing THF, followed by flash column chromatography, afforded two rotamers of 78 (least polar fraction 78a: 122 mg, 38%; most polar fraction 78b: 60 mg, 19%) as orange solids. 78a: 1H NMR (250 MHz, CDCl3): δ (ppm) 7.39–7.27 (m, 5H), 4.70–4.64 (m, 2H), 4.40 (d, J = 11.3 Hz, 1H), 3.84 (s, 3H), 3.72 (d, J = 11.3 Hz, 1H), 3.43 (s, 3H), 3.17–3.14 (m, 1H), 2.90–2.88 (m, 1H), 2.19–1.82 (m, 5H), 1.64 (s, 9H), 1.56–1.35 (m, 2H), 1.22–1.20 (m, 1H); 13C NMR (63 MHz, CDCl3): δ (ppm) 208.8 (C), 171.2 (C), 137.7 (C), 129.1 (2×CH), 128.7 (CH), 126.7 (2×CH), 80.7 (CH), 79.9 (CH), 74.9 (C), 61.3 (CH2), 57.1 (C), 56.9 (CH), 54.7 (CH), 52.9 (CH3), 37.6 (CH3), 34.4 (CH2), 31.5 (CH2), 30.6 (CH2), 30.5 (3×CH3), 28.5 (CH2); IR (neat) 1738 (s), 1238 (m); HRMS (EI, 70 eV) calculated for C24H34IIrN2O2 (M+) 702.1294, found 702.1289. Crystals suitable for X-ray crystal structure determination were obtained by the slow diffusion of pentane into a saturated solution of 78a in DCM. Mp 177–179 ºC. 78b: 1H NMR (250 MHz, CDCl3): δ (ppm) 7.38–7.30 (m, 3H), 7.16–7.13 (m, 2H), 4.70 (br s, 2H), 4.54 (d, J = 11.1 Hz, 1H), 3.86 (s, 3H), 3.54 (d, J = 11.1 Hz, 1H), 3.42 (s, 3H), 3.12–3.10 (m, 1H), 3.03–3.00 (m, 1H), 2.18–1.80 (m, 5H), 1.63 (s, 9H), 1.39–1.20 (m, 3H); 13C NMR (101 MHz, CDCl3): δ (ppm) 209.2 (C), 170.6 (C), 137.4 (C), 129.0 (2×CH), 128.6 (CH), 126.2 (2×CH), 80.9 (CH), 79.7 (CH), 75.6 (C), 60.9 (CH2), 56.9 (C), 56.0 (CH), 54.5 (CH), 52.9 (CH3), 37.8 (CH3), 34.1 (CH2), 31.11 (CH2), 31.06 (CH2), 30.6 (3×CH3), 28.9 (CH2); IR (neat) 1736 (s), 1217 (m); HRMS (EI, 70 eV) calculated for C24H34IIrN2O2 (M+) 702.1294, found 702.1276. Crystals suitable for X-ray crystal structure determination were obtained by the slow diffusion of pentane into a saturated solution of 78b in DCM. Mp 178–180 ºC.

2-Imidazolinium hexafluorophosphate 79. AgPF6 (384 mg, 1.52 mmol) was added to a solution of imidazolinium iodide 69 (612 mg, 1.52 mmol) in DCM (12 mL). While stirring the reaction mixture at rt, a yellow precipitate was formed. After 15 min, the suspension was filtered and the filtrate concentrated in vacuo and washed with pentane to afford salt 79 as a white solid (611 mg, 96%). 1H NMR (250 MHz, CDCl3): δ (ppm) 8.75 (s, 1H), 7.51–7.46 (m,

N

NRh

cod

IPhMeO 2C

N

NIr

cod

IPhMeO 2C

N

N+

PF6−

PhMeO 2C


95

3H), 7.29–7.27 (m, 2H), 4.83 (d, J = 12.2 Hz, 1H), 4.02 (s, 3H), 3.96 (d, J = 12.2 Hz, 1H), 3.29 (s, 3H), 1.50 (s, 9H); 13C NMR (101 MHz, CDCl3): δ (ppm) 168.9 (C), 156.9 (CH), 134.0 (C), 130.1 (CH), 129.9 (2×CH), 126.1 (2×CH), 75.9 (C), 57.83 (C), 57.79 (CH2), 54.0 (CH3), 33.1 (CH3), 27.5 (3×CH3); IR (neat) 1747 (s), 1641 (s), 1267 (m), 839 (s); HRMS (EI, 70 eV) calculated for C16H23N2O2

+ (cation) 275.1754, found 275.1745.

Rh-NHC complex 80. A Schlenk tube was charged with imidazolinium salt 79 (210 mg, 0.5 mmol), KOtBu (56 mg, 0.5 mmol), [Rh(cod)Cl]2 (106 mg, 0.215 mmol), and tetraethylammonium chloride (248 mg, 1.5 mmol). THF (10 mL) was added and the reaction mixture was stirred at rt for 18 h. Then, the mixture was filtered through a pad of celite, concentrated in vacuo and purified using flash column chromatography

(pentane:DCM = 1:2, DCM, DCM:EtOAc = 8:1) to afford 80 (175 mg, 79%) as a 78:22 mixture of rotamers as a yellow/orange solid. Main isomer: 1H NMR (250 MHz, CDCl3): δ (ppm) 7.36–7.19 (m, 5H), 4.89 (br s, 2H), 4.29 (d, J = 11.3 Hz, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.63 (d, J = 11.3 Hz, 1H), 3.49–3.38 (m, 1H), 3.23–3.17 (m, 1H), 2.47–2.13 (m, 4H), 1.94–1.83 (m, 2H), 1.74 (s, 9H), 1.73–1.63 (m, 2H); 13C NMR (63 MHz, CDCl3): δ (ppm) 213.8 (d, J = 45.9 Hz, C), 171.5 (C), 137.7 (C), 129.1 (2×CH), 128.6 (CH), 126.3 (2×CH), 97.4 (d, J = 7.0 Hz, CH), 95.1 (d, J = 6.2 Hz, CH), 75.0 (C), 70.9 (d, J = 15.5 Hz, CH), 67.3 (d, J = 14.5 Hz, CH), 60.6 (CH2), 56.8 (C), 52.8 (CH3), 37.3 (CH3), 33.5 (CH2), 31.3 (CH2), 30.3 (3×CH3), 29.4 (CH2), 27.9 (CH2); IR (neat) 1739 (s), 1475 (m), 1435 (m), 1223 (m); HRMS (EI, 70 eV) calculated for C24H34ClN2O2Rh (M+) 520.1364, found 520.1375.

2-Imidazolinium tosylate 81. According to General Procedure II, alkylation of imidazoline 61 (203 mg, 0.74 mmol) with methyl tosylate (141 mg, 0.74 mmol), followed by washing with pentane, afforded salt 81 (336 mg, 99%) as a white solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 9.70 (s, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 7.4 Hz, 2H), 7.54–7.33 (m, 6H), 7.06 (d, J = 8.0 Hz, 2H), 4.17 (s, 2H), 2.75 (s, 3H), 2.26 (s, 3H), 1.54 (s, 9H); 13C NMR (63 MHz, CDCl3): δ (ppm) 158.8 (CH), 143.9 (C), 141.9 (2×C), 140.2 (2×C), 138.9 (C), 131.0

(2×CH), 129.4 (2×CH), 128.5 (2×CH), 126.0 (2×CH), 124.1 (2×CH), 120.7 (2×CH), 74.8 (C), 57.6 (C), 56.7 (CH2), 30.5 (CH3), 28.0 (3×CH3), 21.2 (CH3); IR (neat): 1475 (s), 1433 (s); HRMS (EI, 70 eV) calculated for C20H23N2

+ (cation) 291.1856, found 291.1849.

Rh-NHC complex 82. A Schlenk tube was charged with imidazolinium salt 81 (231 mg, 0.5 mmol), KOtBu (56 mg, 0.5 mmol), [Rh(cod)Cl]2 (123 mg, 0.25 mmol), and LiCl (64 mg, 1.5 mmol). THF (10 mL) was added and the reaction mixture was stirred at rt for 18 h. Then, the mixture was filtered through a pad of celite and concentrated in vacuo. The residue was taken into DCM, washed with water, dried with Na2SO4, concentrated in vacuo and purified using flash column chromatography (DCM, DCM:EtOAc = 20:1, gradient) to

afford 80 (75 mg, 27%) as a yellow/orange solid. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.68–7.63 (m, 3H), 7.42–7.29 (m, 4H), 7.20 (d, J = 7.4 Hz, 1H), 4.99–4.94 (m, 2H), 4.01 (d, J = 10.8 Hz, 1H), 3.89 (d, J = 10.8 Hz, 1H), 3.44–3.40 (m, 2H), 3.28 (s, 3H), 2.45–2.33 (m, 3H), 2.23–2.20 (m, 1H), 1.97–1.91 (m, 2H), 1.88 (s, 9H), 1.86–1.75 (m, 2H); 13C NMR (63 MHz, CDCl3): δ (ppm) 214.0 (d, J = 45.6 Hz, C), 145.5 (C), 145.0 (C), 140.5 (C), 139.4 (C), 129.47 (CH), 129.45 (CH), 129.0 (CH), 128.3 (CH), 124.6 (CH), 122.8 (CH), 120.3 (CH), 120.0 (CH), 97.4 (d, J = 7.2 Hz, CH), 94.9 (d, J = 7.0 Hz, CH), 74.4 (C), 70.7 (d, J = 15.7 Hz, CH), 67.0 (d, J = 14.5 Hz, CH), 59.6 (CH2), 56.7 (C), 34.6 (CH3), 33.5 (CH2), 31.5 (CH2), 30.4 (3×CH3), 29.4 (CH2),28.0 (CH2); IR (neat) 1473 (s), 1450 (s), 1435 (s); HRMS (EI, 70 eV) calculated for C28H34ClN2Rh (M+) 536.1466, found 536.1473.

Rh-NHC complex 83. A Schlenk tube was charged with imidazolinium chloride 63 (222 mg, 0.5 mmol), KOtBu (56 mg, 0.5 mmol), and [Rh(cod)Cl]2 (118 mg, 0.24 mmol). THF (10 mL) was added and the reaction mixture was stirred at rt for 18 h. Then, the mixture was filtered through a pad of celite, concentrated in vacuo and purified using flash column

N

N+

OTs−

N

NRh

cod

ClPhMeO 2C

N

NRh

cod

Cl

N

NRh

cod

ClMes

Chapter 4

96

chromatography (DCM, DCM:EtOAc = 3:1) to afford 83 (170 mg, 54%) as a yellow/orange solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.55 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H), 7.35–7.17 (m, 5H), 7.10–7.02 (m, 1H), 6.32 (br s, 1H), 6.19 (d, J = 14.3 Hz, 1H), 6.09 (br s, 1H), 5.31 (d, J = 14.2 Hz, 1H), 5.12–5.02 (m, 2H), 3.91 (d, J = 10.7 Hz, 1H), 3.78–3.73 (m, 2H), 3.77 (d, J = 10.7 Hz, 1H), 2.54–2.19 (m, 5H), 1.98 (s, 6H), 1.96 (s, 9H), 1.96 (br s, 3H), 1.70–1.64 (m, 3H); 13C NMR (101 MHz, CDCl3): δ (ppm) 217.8 (d, J = 46.2 Hz, C), 145.1 (C), 144.5 (C), 140.2 (C), 139.7 (C), 139.0 (C), 137.1 (C), 136.7 (C), 128.7 (CH), 128.4 (CH), 128.1 (C), 128.0 (CH), 127.5 (CH), 124.5 (CH), 123.7 (CH), 122.4 (CH), 119.9 (CH), 119.6 (CH), 119.3 (CH), 97.2 (d, J = 7.4 Hz, CH), 94.7 (d, J = 6.9 Hz, CH), 73.8 (C), 69.2 (d, J = 14.7 Hz, CH), 68.8 (d, J = 15.2 Hz, CH), 61.2 (CH2), 57.3 (C), 50.4 (CH2), 32.6 (CH2), 32.3 (CH2), 30.5 (3×CH3), 28.7 (CH2), 28.4 (CH2), 27.4 (CH3), 20.4 (CH3), p-CH3 of mesityl group could not be observed; IR (neat) 1691 (m), 1450 (s), 1200 (s); HRMS (EI, 70 eV) calculated for C37H44ClN2Rh (M+) 654.2248, found 654.2250.

Rh-NHC complex 84. According to General Procedure IV, reaction between imidazolinium bromide 65 (553 mg, 0.5 mmol), KOtBu (56 mg, 0.5 mmol), [Rh(cod)Cl]2 (118 mg, 0.24 mmol) and KI (249 mg, 1.5 mmol), followed by flash column chromatography, afforded 84 (314 mg, 81%) as a 80:20 mixture of rotamers as a yellow solid. Main isomer: 1H NMR (250 MHz, CDCl3): δ (ppm) 7.78 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.49–6.65 (m, 14H), 5.70 (d, J = 14.1 Hz, 1H), 5.37–5.22 (m, 2H),

4.74 (d, J = 14.7 Hz, 1H), 4.46 (d, J = 14.2 Hz, 1H), 4.04–3.93 (m, 1H), 3.92 (d, J = 4.1 Hz, 1H), 3.86–3.78 (m, 2H), 3.84 (s, 3H), 2.52–2.17 (m, 4H), 2.08–1.69 (m, 5H), 0.64 (d, J = 7.2 Hz, 3H), 0.48 (d, J = 7.0 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 217.8 (d, J = 45.6 Hz, C), 159.2 (C), 147.2 (C), 142.0 (C), 140.7 (C), 138.6 (C), 135.7 (2×C), 130.5 (2×CH), 129.8 (2×CH), 129.5 (CH), 128.5 (CH), 127.9 (CH), 127.2 (2×CH), 127.1 (CH), 126.9 (CH), 126.5 (CH), 125.4 (CH), 120.2 (CH), 119.1 (CH), 113.8 (2×CH), 97.5 (d, J = 6.4 Hz, 2×CH), 79.3 (C), 73.6 (CH), 73.1 (d, J = 14.2 Hz, CH), 71.9 (d, J = 14.1 Hz, CH), 55.3 (CH3), 53.5 (CH2), 52.8 (CH2), 32.5 (CH2), 32.1 (CH2), 29.39 (CH2), 29.36 (CH2), 28.7 (CH), 19.9 (CH3), 18.0 (CH3); IR (neat) 1512 (s), 1450 (s), 1248 (s); HRMS (EI, 70 eV) calculated for C33H32N2ORh (M−(I+cod)+) 575.1570, found 575.1564 (The molecular ion is hardly detectable in the mass spectrometer). Crystals suitable for X-ray crystal structure determination were obtained by the slow diffusion of pentane into a saturated solution of 84 in DCM. Mp 186–187 ºC.

Rh-NHC complex 85. According to General Procedure IV, reaction between imidazolinium iodide 67 (166 mg, 0.25 mmol), KOtBu (28 mg, 0.25 mmol), [Rh(cod)Cl]2 (59 mg, 0.12 mmol) and KI (125 mg, 0.75 mmol), followed by flash column chromatography, afforded 85 (173 mg, 82%) as a 58:42 mixture of rotamers as an orange/yellow solid. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.87–7.85 (m, 1HB), 7.67–7.62 (m, 1HA+2HB), 7.55–7.34 (m, 7HA+4HB), 7.26–7.21 (m, 1HB), 7.11–7.06 (m, 1HB), 6.99–

6.92 (m, 3HA+1HB), 6.91–6.88 (m, 1HA+1HB), 6.81 (d, J = 7.6 Hz, 1HB), 6.54 (d, J = 16.9 Hz, 1HA), 5.90 (d, J = 15.3 Hz, 1HB), 5.81 (d, J = 17.0 Hz, 1HA), 5.32 (s, 1HA), 5.31–5.26 (m, 1HB), 5.27 (d, J = 15.2 Hz, 1HB), 5.23–5.13 (m, 2HA+1HB), 5.09 (s, 1HB), 4.74 (br s, 1HA), 4.14 (br s, 1HA), 3.94 (br s, 1HB), 3.83 (s, 3HA), 3.81 (s, 3HB), 3.76 (s, 5HA), 3.77–3.75 (m, 1HB), 3.75–3.72 (m, 1HA), 3.68–3.59 (m, 2HA+1HB), 3.60 (s, 5HB), 3.58–3.50 (m, 2HB), 3.03 (br s, 1HA), 3.01 (br s, 1HB), 2.94 (s, 3HA), 2.93 (s, 3HB), 2.37–2.22 (m, 2HA+1HB), 2.21–2.12 (m, 3HB), 2.06–1.92 (m, 1HA+1HB), 1.87–1.74 (m, 4HA+2HB), 1.56–1.47 (m, 1HB); 13C NMR (101 MHz, CDCl3): δ (ppm) 216.6 (d, J = 45.0 Hz, CB), 216.4 (d, J = 44.7 Hz, CA), 158.8 (CB), 158.5 (CA), 147.0 (CA), 145.2 (CB), 141.9 (CB), 141.0 (CB), 140.9 (CA), 140.7 (CB), 140.3 (CA), 139.9 (CA), 131.8 (CA+CB), 129.8 (CHB), 129.6 (CHA), 129.5 (CHB), 129.2 (2×CHB), 129.0 (CHA), 128.70 (CHB), 128.66 (CHA), 128.2 (CHA), 127.2 (CHA), 127.0 (CHB), 126.9 (2×CHA), 125.9 (CHB), 124.9 (CHB), 122.2 (CHA), 120.3 (CHA), 120.1 (CHB), 119.9 (CHB), 119.3 (CHA), 114.3 (2×CHA), 113.6 (2×CHB), 97.4 (d, J = 6.2 Hz, CHB), 97.3 (d, J = 6.6 Hz, CHB), 97.2 (d, J = 6.5 Hz, CHA), 96.8 (d, J = 6.5 Hz, CHA), 84.4 (CA), 82.2 (CA), 81.4 (CB), 80.4 (CB), 72.7 (d, J = 14.2 Hz, CHA), 72.3 (d, J = 14.4 Hz, CHB), 71.9 (d, J = 13.9 Hz, CHA), 71.7 (d, J = 14.2 Hz, CHB), 70.7 (CHA), 70.2 (CHB), 68.78 (CHB), 68.75 (CHA), 68.6 (5×CHB), 68.5 (5×CHA), 68.4 (CHB), 67.9 (CHA), 67.6 (CHA), 67.0 (CHB), 66.6 (CHB), 66.4 (CHA), 55.3

N

NPMB

Rhcod

IPh

N

NPMBF c

Rhcod

I


97

(CH3A+CH3

B), 52.0 (CH2B), 51.5 (CH2

A), 33.4 (CH3B), 33.2 (CH2

B), 33.1 (CH3A), 32.9 (CH2

A), 31.3 (CH2A+CH2

B), 30.2 (CH2

B), 30.0 (CH2A), 28.7 (CH2

A), 28.5 (CH2B); IR (neat) 1612 (m), 1512 (s), 1489 (m), 1450 (s), 1246 (s).

HRMS (EI, 70 eV) calculated for C42H42FeIN2ORh (M+) 876.0746, found 876.0768. Rh-NHC complex 86. According to General Procedure IV, reaction between imidazolinium iodide 71 (208 mg, 0.5 mmol), KOtBu (56 mg, 0.5 mmol), [Rh(cod)Cl]2 (118 mg, 0.24 mmol) and KI (249 mg, 1.5 mmol), followed by flash column chromatography, afforded 86 (238 mg, 79%) as a 82:18 mixture of rotamers as an orange/yellow solid. Main isomer: 1H NMR (250

MHz, CDCl3): δ (ppm) 8.18 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 5.65–5.50 (m, 1H), 5.15–5.03 (m, 2H), 4.34 (d, J = 3.9 Hz, 1H), 3.74–3.65 (m, 1H), 3.60–3.42 (m, 2H), 3.25 (s, 3H), 2.28–2.11 (m, 4H), 2.05–1.69 (m, 5H), 1.31 (d, J = 7.0 Hz, 3H), 1.19 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 213.7 (d, J = 44.5 Hz, C), 147.8 (C), 147.3 (C), 128.1 (2×CH), 124.5 (2×CH), 97.7 (d, J = 6.4 Hz, CH), 97.1 (d, J = 6.3 Hz, CH), 72.1 (d, J = 18.5 Hz, CH), 71.2 (d, J = 15.8 Hz, CH), 71.0 (CH), 66.3 (CH), 51.5 (CH), 35.9 (CH3), 32.3 (CH2), 32.2 (CH2), 30.7 (CH), 29.4 (CH2), 29.3 (CH2), 23.1 (CH3), 20.3 (CH3), 18.3 (CH3), 13.6 (CH3); IR (neat) 1523 (s), 1446 (m), 1346 (s), 1188 (m); HRMS (EI, 70 eV) calculated for C24H35IN3O2Rh (M+) 627.0829, found 627.0803. Crystals suitable for X-ray crystal structure determination were obtained by the slow diffusion of pentane into a saturated solution of 86 in DCM. Mp 136–139 ºC.

Rh-NHC complex 87. According to General Procedure IV, reaction between imidazolium iodide 73 (112 mg, 0.27 mmol), KOtBu (31 mg, 0.28 mmol), [Rh(cod)Cl]2 (67 mg, 0.135 mmol) and KI (135 mg, 0.81 mmol), followed by flash column chromatography, afforded 87 (80 mg, 46%) as an orange/yellow solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 8.25 (d, J =

7.5 Hz, 2H), 7.43 (d, J = 7.4 Hz, 2H), 6.19–5.96 (m, 1H), 5.23–5.04 (m, 2H), 3.55 (s, 3H), 3.52–3.40 (m, 2H), 3.29–3.08 (m, 1H), 2.36–2.11 (m, 4H), 1.95–1.63 (m, 4H), 1.62 (d, J = 7.9 Hz, 3H), 1.58 (d, J = 9.6 Hz, 3H), 1.04–0.83 (m, 6H); 13C NMR (63 MHz, CDCl3): δ (ppm) 180.0 (d, J = 48.8 Hz, C), 148.3 (C), 137.1 (C), 137.0 (C), 132.6 (2×CH), 129.3 (C), 123.7 (2×CH), 96.2 (d, J = 6.8 Hz, CH), 95.7 (d, J = 6.8 Hz, CH), 71.5 (d, J = 14.4 Hz, CH), 70.8 (d, J = 14.0 Hz, CH), 54.0 (CH), 35.9 (CH3), 32.4 (CH2), 32.1 (CH2), 29.7 (CH2), 29.4 (CH2), 25.4 (CH), 23.1 (CH3), 22.8 (CH3), 22.6 (CH3), 21.8 (CH3); IR (neat) 1522 (s), 1342 (s); HRMS (EI, 70 eV) calculated for C24H33IN3O2Rh (M+) 625.0672, found 625.0653. Crystals suitable for X-ray crystal structure determination were obtained by the slow diffusion of pentane into a saturated solution of 87 in DCM. Mp 223–225 ºC (decomp.) General Procedure V for the Synthesis of Imidazolidine-2-thiones: Reactions were carried out at a concentration of 0.04 M of imdazolinium salt in dry THF. A Schlenk tube was charged with imidazolinium halide (1 equiv.), KOtBu (1 equiv.) and S8 (1 equiv.). THF was added and the reaction mixture was stirred at rt for 2 h. Then, water was added and the mixture was extracted with EtOAc (3×). The organic layers were dried with Na2SO4 and concentrated in vacuo. The crude product was put on a pre-packed silica column. Excess sulfur was eluted with toluene and then the product was eluted with toluene:EtOAc = 20:1, gradient.

Imidazolidine-2-thione 89. According to General Procedure V, reaction between imidazolinium iodide 62 (93 mg, 0.22 mmol), KOtBu (25 mg, 0.22 mmol), and S8 (57 mg, 0.22 mmol), followed by flash column chromatography, afforded 89 (64 mg, 89%) as a white solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.71 (d, J = 7.5 Hz, 2H), 7.53–7.35 (m, 6H), 3.96 (s, 2H), 2.58 (s, 3H), 1.74 (s, 9H); 13C NMR (63 MHz, CDCl3): δ (ppm) 182.5 (C), 143.4 (2×C), 139.0 (2×C), 128.7 (2×CH), 127.4 (2×CH), 122.8 (2×CH), 119.3 (2×CH), 70.9 (C),

55.8 (C), 55.5 (CH2), 29.2 (CH3), 27.0 (3×CH3); IR (neat) 1471 (m), 1446 (m), 14008 (s), 1309 (s); HRMS (EI, 70 eV) calculated for C20H22N2S (M+) 322.1504, found 322.1493.

N

N

PNPRh

cod

I

N

N

PNP

Rhcod

I

N

NS

Chapter 4

98

Imidazolidine-2-thione 90. According to General Procedure V, reaction between imidazolinium iodide 63 (90 mg, 0.20 mmol), KOtBu (25 mg, 0.22 mmol), and S8 (53 mg, 0.20 mmol), followed by flash column chromatography, afforded 90 (66 mg, 76%) as a white solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.55 (d, J = 7.6 Hz, 2H), 7.32–7.26 (m, 2H), 7.18 (d, J = 7.4 Hz, 2H), 7.09–7.06 (m, 2H), 6.33 (s, 2H), 4.78 (s, 2H), 3.77 (s, 2H), 2.06 (s, 3H), 1.83 (s, 6H), 1.74 (s, 9H); 13C NMR (63 MHz, CDCl3): δ (ppm) 184.2 (C), 143.9 (2×C),

139.5 (2×C), 137.5 (2×C), 135.9 (C), 130.4 (C), 128.9 (2×CH), 128.3 (2×CH), 127.6 (2×CH), 123.8 (2×CH), 119.7 (2×CH), 71.9 (C), 57.1 (CH2), 57.0 (C), 43.6 (CH2), 28.0 (3×CH3), 20.5 (CH3), 19.7 (2×CH3); IR (KBr) 1450 (m), 1402 (m), 1362 (s), 1308 (s), 1213 (s); HRMS (EI, 70 eV) calculated for C29H32N2S (M+) 440.2286, found 440.2265.

Imidazolidine-2-thione 91. According to General Procedure V, reaction between imidazolinium iodide 65 (553 mg, 1.0 mmol), KOtBu (118 mg, 1.05 mmol), and S8 (256 mg, 1.0 mmol), followed by flash column chromatography, afforded 91 (449 mg, 89%) as a white solid. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.67 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.48–7.36 (m, 4H), 7.29–7.13 (m, 2H), 7.07–6.87 (m, 8H), 6.76 (d, J = 7.6 Hz, 1H), 6.00 (d, J = 15.3 Hz, 1H), 4.98 (d, J = 15.1 Hz, 1H), 4.48 (d, J = 15.3 Hz, 1H), 3.97 (d, J = 4.6 Hz, 1H),

3.86 (s, 3H), 3.70 (d, J = 15.1 Hz, 1H), 2.06–1.98 (m, 1H), 0.57 (d, J = 7.1 Hz, 3H), 0.47 (d, J = 7.0 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 186.6 (C), 159.0 (C), 144.9 (C), 141.5 (C), 141.0 (C), 140.3 (C), 138.6 (C), 129.7 (CH), 129.4 (2×CH), 129.2 (CH), 128.3 (C), 128.0 (2×CH), 127.6 (3×CH), 127.5 (CH), 127.2 (CH), 126.6 (CH), 124.9 (CH), 120.0 (CH), 119.8 (CH), 114.0 (2×CH), 76.5 (C), 70.3 (CH), 55.3 (CH3), 50.4 (CH2), 48.3 (CH2), 28.2 (CH), 19.3 (CH3), 18.5 (CH3); IR (KBr) 161 (m), 1512 (s), 1441 (s), 1248 (s); HRMS (EI, 70 eV) calculated for C33H32N2OS (M+) 504.2235, found 504.2229; Elemental analysis: calculated for C33H32N2OS (%): C 78.53, H 6.39, N 5.55, S 6.35, found C 77.37, H 6.88, N 5.22, S 6.47. General Procedure VI for the Synthesis of Rh(CO)2I(NHC) Complexes: A Schlenk tube was charged with Rh(cod)I(NHC) complex (0.05–0.1 mmol). Dry THF (8–15 mL) was added and CO was bubbled through the yellow solution until it was pale yellow (10–15 min). The reaction mixture was concentrated in vacuo, and the product was obtained as (an often air-sensitive) white foam, which was immediately measured using NMR (which showed quantitative conversion) and IR.

Rh-NHC complex 94. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.85–7.73 (m, 1H), 7.70–7.55 (m, 2H), 7.44–7.22 (m, 5H), 4.10 (s, 2H), 2.76 (s, 3H), 1.63 (s, 9H); 13C NMR (101 MHz, CDCl3): δ (ppm) 202.2 (d, J = 36.7 Hz, C), 187.5 (d, J = 53.6 Hz, C), 181.9 (d, J = 79.4 Hz, C), 144.7 (C), 144.6 (C), 140.5 (C), 139.7 (C), 129.9 (CH), 129.8 (CH), 129.1 (CH), 128.7 (CH), 124.9 (CH), 123.2 (CH), 120.5 (CH), 120.1 (CH), 74.7 (C), 59.8 (CH2), 56.6 (C), 35.4 (CH3), 30.6 (3×CH3); IR (KBr) 2069 (s), 1991 (s); HRMS (EI, 70

eV) calculated for C22H22IN2O2Rh (M+) 575.9781, found 575.9784; Elemental analysis: calculated for C22H22IN2O2Rh (%): C 45.86, H 3.85, N 4.86, found C 45.86, H 3.91, N 4.99.

Rh-NHC complex 95. This complex was isolated as a 73:27 mixture of rotamers. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.33 (d, J = 7.3 Hz, 1HA), 7.78 (d, J = 6.8 Hz, 1HB), 7.73–6.81 (m, 16HA+16HB), 6.04 (d, J = 15.9 Hz, 1HA), 5.78 (d, J = 14.9 Hz, 1HB), 4.86 (d, J = 14.4 Hz, 1HA), 4.73 (d, J = 15.2 Hz, 1HB), 4.71 (d, J = 14.9 Hz, 1HB), 4.53 (d, J = 15.4 Hz, 1HA), 4.31 (d, J = 4.3 Hz, 1HA), 4.07 (d, J = 14.6 Hz, 1HB), 4.00 (br s, 1HB), 3.83 (s, 3HA), 3.80 (s, 3HB), 3.57 (d, J = 14.6 Hz, 1HA), 2.03–1.85 (m, 1HA+1HB), 0.80 (d, J =

6.6 Hz, 3HB), 0.74 (d, J = 7.0 Hz, 3HB), .70 (d, J = 6.8 Hz, 3HA), 0.42 (d, J = 7.0 Hz, 3HA); 13C NMR (101 MHz, CDCl3): δ (ppm) 207.5 (d, J = 38.5 Hz, CA), 206.5 (d, J = 37.2 Hz, CB), 187.2 (d, J = 52.5 Hz, CA), 187.0 (d, J = 51.3 Hz, CB), 181.6 (d, J = 79.0 Hz, CA), 181.1 (d, J = 77.5 Hz, CB), 159.4 (CB), 159.3 (CA), 146.2 (CA+CB), 141.8

N

NS

Mes

N

NPMB

S

Ph

N

NPMB

Rh COI

COPh

N

NRh COI

CO


99

(CB), 141.1 (CA), 140.6 (CA), 140.0 (CA), 139.9 (CB), 139.0 (CB), 136.3 (CA), 136.0 (CB), 130.3 (CHA), 130.0 (CHA), 129.8 (CHB), 129.6 (CHA), 129.5 (3×CHB), 129.3 (2×CHB), 128.9 (2×CHA), 128.5 (CHB), 128.3. (2×CHA), 127.9 (2×CHA+2×CHB), 127.4 (CHA), 127.6 (CHB), 127.5 (CHA), 127.4 (CHA), 127.3 (CHB), 126.9 (CHB), 126.83 (CA), 126.79 (CB), 125.0 (CHB), 124.5 (CHA), 120.3 (CHB), 120.00 (CHA), 119.95 (CHA), 119.6 (CHB), 114.4 (2×CHA), 113.9 (2×CHB), 80.7 (CB), 80.3 (CA), 75.0 (CHB), 73.6 (CHA), 55.33 (CH3

A), 55.28 (CH3B), 54.4 (CH2

B), 53.3 (CH2

A), 52.2 (CH2B), 51.7 (CH2

A), 29.5 (CHB), 27.7 (CHA), 21.1 (CH3B), 18.8 (CH3

A), 18.4 (CH3B), 18.1

(CH3A); IR (KBr) 2067 (s), 1996 (s); HRMS (EI, 70 eV) calculated for C33H32IN2O1Rh (M−(I+2×CO)+) 575.1570,

found 575.1563 (The molecular ion is not detectable in the mass spectrometer).

Rh-NHC complex 96. This complex was isolated as a 62:38 mixture of rotamers. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.45–7.35 (m, 4HA+4HB), 7.19–7.16 (m, 1HA+1HB), 4.68 (d, J = 11.2 Hz, 1HB), 4.61 (d, J = 11.4 Hz, 1HA), 3.92 (s, 3HA+3HB), 3.85 (d, J = 11.6 Hz, 1HA), 3.73 (d, J = 11.2 Hz, 1HB), 3.31 (s, 3HA), 3.30 (s, 3HB), 1.59 (s, 9HA),

1.58 (s, 9HB); 13C NMR (101 MHz, CDCl3): δ (ppm) 202.8 (d, J =38.0 Hz, CB), 202.5 (d, J = 37.5 Hz, CA), 187.4 (d, J = 53.7 Hz, CB), 187.3 (d, J = 53.6 Hz, CA), 181.8 (d, J = 79.4 Hz, CB), 181.4 (d, J = 79.8 Hz, CA), 171.1 (CA), 169.9 (CB), 129.3 (2×CHB), 129.2 (2×CHA), 129.0 (CHB), 128.9 (CHA), 126.6 (2×CHA), 126.1 (2×CHB), 76.2 (CB), 75.4 (CA), 61.1 (CH2

A), 60.6 (CH2B), 56.8 (CA), 56.7 (CB), 53.3 (CH3

B), 53.1 (CH3A), 38.5 (CH3

B), 38.0 (CH3A),

30.4 (3×CH3A+3×CH3

B); IR (neat) 2067 (s), 1994 (s); HRMS (EI, 70 eV) calculated for C18H22IN2O4Rh (M+) 559.9679, found 559.9686.

Rh-NHC complex 97. This complex was isolated as a 86:16 mixture of rotamers. Main isomer: 1H NMR (250 MHz, CDCl3): δ (ppm) 8.21 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 4.93–4.78 (m, 1H), 4.46 (d, J = 4.3 Hz, 1H), 3.68 (dd, J = 4.2, 3.7 Hz, 1H), 3.03 (s, 3H), 2.27–2.05 (m, 1H), 1.32 (d, J = 7.0 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 7.0 Hz,

3H), 0.88 (d, J = 6.8 Hz, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 201.3 (d, J = 37.4 Hz, C), 187.4 (d, J = 52.5 Hz, C), 181.7 (d, J = 78.5 Hz, C), 148.1 (C), 146.5 (C), 128.0 (2×CH), 124.7 (2×CH), 73.4 (CH), 66.0 (CH), 51.6 (CH), 36.0 (CH3), 29.7 (CH), 23.0 (CH3), 19.7(CH3), 17.9 (CH3), 13.9 (CH3); IR (neat) 2070 (s), 1998 (s). Crystal Structure Determinations. X-ray intensities were measured on a Nonius KappaCCD diffractometer with rotating anode (graphite monochromator, λ = 0.71073 Å) up to a resolution of (sin θ/λ)max = 0.65 Å−1. The structures were solved with automated Patterson methods74 and refined with SHELXL-9775 against F2 of all reflections. Non hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were introduced in calculated positions (84-II) or located in the difference Fourier map (all other structures). Geometry calculations and checking for higher symmetry was performed with the PLATON program.76 Further experimental details are given in Table 9. In 75 the H-atoms of the cod ligand were refined freely with isotropic displacement parameters; all other H-atoms were refined with a riding model. In 78a and 78b the H-atoms at C3 and at the cod double bonds were refined freely with isotropic displacement parameters; all other H-atoms were refined with a riding model. Datasets for 84-I and 84-II were measured on the same crystal at different temperatures. While over a wide temperature range (110–250 K) both phases are present, at 200 K the P21/n phase (84-I) has higher intensity and at 110 K the P21 phase (84-II). Only these major components were integrated using the HKL2000 software.77 84-II was refined in a non-standard setting of space group P21 with an origin shift of (0.25, 0, 0.25) to obtain consistent coordinates with respect to the high temperature phase P21/n of 84-I (group/subgroup relationship of the phase transition). In 84-I the H-atoms at C3 and at the cod double bonds were refined freely with isotropic displacement parameters; all other H-atoms were refined with a riding model. In 84-II all H-atoms were refined with a riding model. 84-II was refined as an inversion twin resulting in a Flack parameter x=0.183(9).78

N

NRh COI

COPhMeO 2C

N

NRh COI

COPNP

Chapter 4

100


101

The crystal structure of 86 contains large voids (596.4 Å3/unit cell) filled with disordered solvent molecules. Their contribution to the structure factors was secured by back-Fourier transformation using the SQUEEZE routine of the program PLATON,76 accounting for 137 electrons / unit cell. The H-atoms at the cod double bonds were refined freely with isotropic displacement parameters; all other H-atoms were refined with a riding model. In 87 the H-atoms at the cod double bonds were refined freely with isotropic displacement parameters; all other H-atoms were refined with a riding model. CCDC 612936 (compound 75), 612937 (78a), 612938 (78b), 612939 (84-I), 612940 (84-II), 612941 (86) and 612942 (87) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.


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Weskamp, T.; Böhm, V. P. W. Adv Organomet. Chem. 2001, 48, 1–69. c) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.; Yang, C.; Nolan, S. J. Organomet. Chem. 2002, 653, 69–82. d) Bedford, R. B.; Cazin, C. S. J.; Holder, D. Coord. Chem. Rev. 2004, 248, 2283–2321. e) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29. f) Peris, E.; Crabtree, R. H. Coord. Chem. Rev. 2004, 248 2239–2246. g) Crabtree, R. H. J. Organomet. Chem. 2005, 690, 5451–5457.

[3] Herrmann, W. A.; Roesky, P. W.; Elison, M.; Artus, G. R.; Öfele, K. Organometallics 1995, 14, 1085–1086. [4] Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225–3228. [5] Süßner, M.; Plenio, H. Angew. Chem. Int. Ed. 2005, 44, 6885–6888. [6] Hong, S. H.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 3508–3509. [7] Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. Angew. Chem. Int. Ed. 2003, 42, 3690–3693. [8] a) Despagnet-Ayoub, E.; Grubbs, R. H. J. Am. Chem. Soc. 2004, 126, 10198–10199. b) Despagnet-Ayoub,

E.; Grubbs, R. H. Organometallics 2005, 24, 338–340. [9] a) Alder, R. W.; Blake, M. E; Bortolotti, C.; Butts, C. P.; Linehan, E.; Oliva, J. M.; Orpen, A. G.; Quayle, M.

J. Chem. Comm. 1999, 241–242. b) Guillen, F.; Winn, C. L.; Alexakis, A. Tetrahedron: Asymmetry 2001, 12, 2083–2086. c) Bazinet, P.; Yap, G. P. A.; Richeson, D. S. J. Am. Chem. Soc. 2003, 125, 13314–13315.

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[12] a) Lemal, D. M.; Lovald, R. A.; Kawano, K. I. J. Am. CHem. Soc. 1964, 86, 2518. b) Winberg, H. E.; Carnahan, J. E.; Coffman, D. D.; Brown, M. J. Am. Chem. Soc. 1965, 87, 2055. c) Wiberg, N. Angew. Chem. Int. Ed. Engl. 1968, 7, 766.

[13] Wanzlick, H.-W.; Schönherr, H.-J. Angew. Chem. Int. Ed. Engl. 1968, 7, 141. [14] Öfele, K. J. Organomet. Chem. 1968, 12, P42. [15] Cardin D. J.; Çetinkaya, B.; Lappert, M. F.; Manojlovic-Muir, Lj.; Muir, K. W. J. Chem. Soc., Chem.

Commun. 1971, 400. [16] Lappert, M. F. J. Organomet. Chem. 2005, 690, 5467–5473 and references therein. [17] Arduengo III, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361–363. [18] Arduengo III, A. J.; Goerlich, J.; Marshall, W. J. Am. Chem. Soc. 1995, 117, 11027–11028. [19] a) Denk, M. K.; Thadani, A.; Hatano, K.; Lough, A. J. Angew. Chem. Int. Ed. 1997, 36, 2607–2609. b) Denk,

M. K.; Hatamo, K.; Ma, M. Tetrahedron Lett. 1999, 40, 2057–2060. c) Hahn, F. E.; Paas, M.; Le Van, D.; Lügger, T. Angew. Chem. Int. Ed. 2003, 42, 5243–5246.

[20] Hahn, F. E.; Wittenbecher, L.; Böse, R.; Bläser, D. Chem. Eur. J. 1999, 5, 1931–1935.

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[21] a) Herrmann, W. A.; Fischer, J.; Elison, M.; Köcher, C.; Öfele, K. (Hoechst AG), DE 4447066.5 A1, 1994; EP 0721953 A1 [Chem. Abstr. 1996, 125, 143019y]. b) Herrmann, W. A.; Fischer, J.; Elison, M.; Köcher, C. (Hoechst AG), DE 4447068.1 A1, 1994; EP 0719758 A1; US 5.703.269, 1997 [Chem. Abstr. 1996, 125, 167571y]. c) Herrmann, W. A.; Elison, M.; Fischer, J.; Köcher, C. (Celanese GmbH), DE 4447067.3 A1, 1994; EP 0719753 A1, 1995 [Chem. Abstr. 1996, 125, 167338c]. d) Herrmann, W. A.; Elison, M.; Fischer, J.; Köcher, C. (Hoechst AG), DE 4447070.3 A1, 1994; EP 0721951 A1 [Chem. Abstr. 1996, 125, 143016v].

[22] It should be mentioned that detailed experimental and computational studies of the more subtle effects at work in the bonding of NHCs have been performed: Tafipolsky, M.; Scherer, W.; Öfele, K.; Artus, G.; Pedersen, B.; Herrmann, W. A.; McGrady, G. S. J. Am. Chem. Soc. 2002, 124, 5865–5880 and references cited therein.

[23] Bourissou, D; Guerret, O.; Gabbaï, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 1, 39–91. [24] These data are summarised in the following reviews: a) Kirmse, W. Angew. Chem. Int. Ed. 2004, 43, 1767–

1769. b) ref. 23. [25] Strictly spoken, pKa’s correspond with the acidity of the conjugated imidazolium salt, but it is also common

practice to refer to the pKa of a base when dealing with ligand basicity. [26] Alder, R. W.; Allen, P. R.; Williams, S. J. J. Chem. Soc., Chem. Commun. 1995, 1267–1268. [27] Kim, Y.-J.; Streitwieser, A. J. Am. Chem. Soc. 2002, 124, 5757–5761. [28] Amyes, T. L.; Diver, S. T.; Richard, J. P.; Rivas, F. M.; Toth, K. J. Am .Chem. Soc. 2004, 126, 4366–4374. [29] Magill, A. M.; Cavell, K. J.; Yates, B. F. J. Am. Chem. Soc. 2004, 126, 8717–8724. [30] Carter, E. A.; Goddard, W. A. J. Phys. Chem. 1986, 90, 998–1001. [31] Taton, T. A.; Chen, P. Angew. Chem. Int. Ed. Engl. 1996, 35, 1011–1013. [32] Chen, P. Adv. Carbene Chem. 1998, 2, 45–75. [33] a) Alder, R. W.; Blake, M. E.; Chaker, L.; Harvey, J. N.; Paolini, F.; Schütz, J. Angew. Chem. Int. Ed. 2004,

43, 5896–5911 and references cited therein. b) Hahn, F. E.; Paas, M.; Fröhlich, R. Chem. Eur. J. 2005, 11, 5080–5085.

[34] Hahn, F. E.; Wittenbecher, L.; Le Van, D.; Fröhlich, R. Angew. Chem. Int. Ed. 2000, 39, 541–544. [35] a) Denk, M. K.; Rodezno, J. M.; Gupta, S.; Lough, A. J. J. Organomet. Chem. 2001, 617–618, 242–253. b) It

must be noted that the air oxidation of carbenes of type A and B can be catalysed by CuCl. [36] Also the dimers of carbenes of type B and C are well known to undergo air oxidation to the corresponding

urea derivatives. See for example a) Hitchcock, P. B.; Lappert, M. F.; Terreros, P.; Wainwright, K. P. J. Chem. Soc. Chem. Commun. 1980, 24, 1180–1181. b) Cetinkaya, B.; Cetinkaya, E.; Kuecuekbay, H.; Durmaz, R. Arzneim. Forsch. 1996, 46, 1154–1157.

[37] Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem. Int. Ed. 2004, 43, 5130–5135 and references cited therein. [38] Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res.

2003, 36, 899–907. [39] a) Weskamp, T.; Kohl, F. J.; Hieringer, W.; Gleich, D.; Herrmann, W. A. Angew. Chem., Int. Ed. 1999, 38,

2416–2419. b) Schwarz, J.; Böhm, V. P. W.; Gardiner, M. G.; Grosche, M.; Herrmann, W. A.; Hieringer, W.; Raudaschl-Sieber, G. Chem. Eur. J. 2000, 6, 1773–1780. c) Öfele, K.; Herrmann, W. A.; Mihalios, D.; Elison, M.; Herdtweck, E.; Sherer, W.; Mink, J. J. Organomet. Chem. 1993, 459, 177–184.

[40] Cavallo, L.; Corea, A.; Costabile, C.; Jacobsen, H. J. Organomet. Chem. 2005, 690, 5407–5413 and references cited therein.

[41] Herrmann, W.A.; Runte, O.; Artus, G. J. Organomet. Chem. 1995, 501, C1–C4 [42] a) Hu, X. L.; Castro-Rodriquez, I.; Olsen, K.; Meyer, K. Organometallics 2004, 23, 755–764. b) Frenking,

G.; Solà, M.; Vyboishchikov, S. F. J. Organomet. Chem. 2005, 690, 6178–6204 and references cited therein. c) Termaten, A. T.; Schakel, M.; Ehlers, A. W.; Lutz, M.; Spek, A. L.; Lammertsma, K. Chem. Eur. J. 2003, 9, 3577–3582.

[43] Tafipolski, M.; Scherer, W.; Öfele, K.; Artus, G.; Pedersen, B.; Herrmann, W. A.; McGrady, S. S. J. Am. Chem. Soc. 2002, 124, 5865–5880.

[44] Crudden, C. M.; Allen, D. P. Coord. Chem. Rev. 2004, 248, 2247–2273 and references cited therein.


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[45] Arduengo III, A. J.; Krafczyk, R.; Schmutzler, R.; Craig, H. A.; Goerlich, J. R.; Marshall, W. J.; Unverzagt, M. Tetrahedron 1999, 55, 14523–14534.

[46] Weskamp, T.; Herrmann, W. A. J. Organomet. Chem. 2000, 600, 12–22. [47] Delaude, L.; Szypa, M.; Demonceau, A.; Noels, A. F. Adv. Synth. Catal. 2002, 344, 749–756. [48] Kuhn, N.; Kratz, T. Synthesis 1993, 561–562. [49] Rivas, F. M.; Riaz, U.; Giessert, A.; Smulik, J. A.; Diver, S. T. Org. Lett. 2001, 3, 2673–2676. [50] a) Wang, H. M. J.; Lin, I. J. B. Organometallics 1998, 17, 972–975. b) Pytkowicz, J.; Roland, S.; Mangeney,

P. J. Organomet. Chem. 2001, 631, 157–163. [51] Garrison, J. C.; Youngs, W. J. Chem. Rev. 2005, 105, 3978–4008. [52] McGuinness, D. S.; Cavell, K. J.; Yates, B. F.; Skelton, B. W.; White, A. H. J. Am. Chem. Soc. 2001, 123,

34, 8317–8328. [53] Fürstner, A.; Seidel, G.; Kremzow, D.; Lehmann, C. W. Organometallics 2003, 22, 907–909. [54] Clement, N. D.; Cavell, K. J.; Jones, C.; Elsevier, C. J. Angew. Chem. Int. Ed. 2004, 43, 1277–1279. [55] Simms, R. W.; Drewitt, M. J.; Baird, M. C. Organometallics 2002, 21, 2958–2963. [56] Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247–2250. [57] Herrmann, W. A.; Böhm, V. P. W.; Gstöttmayr, C. W. K.; Grosche, M.; Reisinger, C. P.; Weskamp, T. J.

Organomet. Chem. 2001, 618, 616–628. [58] a) Bon, R. S.; Hong, C.; Bouma, M. J.; Schmitz, R. F.; de Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Orru,

R. V. A. Org. Lett. 2003, 5, 3759–3762. b) Bon, R. S.; van Vliet, B.; Sprenkels, N. E.; Scmitz, R. F.; de Kanter, F. J. J.; Stevens, C. V.; Swart, M.; Bickelhaupt, F. M.; Groen, M. B.; Orru, R. V. A. J. Org. Chem. 2005, 70, 3542–3553.

[59] a) Bildstein, B.; Malaun, M.; Kopacka, H.; Ongania, K.-H.; Wurst, K. J. Organomet. Chem. 1998, 552, 45–61. b) Bildstein, B.; Malaun, M.; Hopacka, H.; Wurst, K.; Mitterböck, M.; Ongania, K.-H.; Opromolla, G.; Zanello, P. Organometallics 1999, 18, 4325–4336. c) Bolm, C.; Kesselgruber, M.; Raabe, G. Organometallics, 2002, 21, 707–710. d) Seo, H.; Park, H.; Kim, B. Y.; Lee, J. H.; Son, S. U.; Chung, Y. K. Organometallics 2003, 22, 618–620.

[60] Arduengo III, A. J.; Tapu, D.; Marshall, W. J. Angew. Chem. Int. Ed. 2005, 44, 7240–7244. [61] Small differences in ratios depicted in Table 3 may be attributed to small losses during chromatographic

purification. [62] Furthermore, heating a solution of a single rotamer of 78 in toluene-d8 at 150 ºC (microwave) for 30 min

does not provide a mixture of rotamers. At 200 ºC, the product decomposes completely. [63] Baker, M. V.; Brayshaw, S. K.; Skelton, B. W.; White, A. H. Inorg. Chim. Acta 2004, 357, 2841–2849. [64] a) Chianese, A. R.; Crabtree, R. H. Organometallics 2005, 24, 4432–4436. b) Viviano, M.; Mas-Marzá, E.;

Sanaú, M.; Peris, E. Organometallics 2006, 25, 3063–3069. c) Herrmann, W. A.; Baskakov, D.; Herdtweck, E.; Hoffmann, S. D.; Bunlaksananusorn, T.; Rampf, F.; Rodefeld, L. Organometallics, 2006, 25, 2449–2456.

[65] a) Evans, P. A.; Baum, E. W.; Fazal, A. N.; Pink, M. Chem. Comm. 2005, 63–65. b) Lee, S. I.; Park, S. Y.; Park, J. H.; Jung, I. G.; Choi, S. Y.; Chung, Y. K. J. Org. Chem. 2006, 71, 91–96.

[66] Herrmann, W. A.; Schütz, J.; Frey, G. D.; Herdtweck, E. Organometallics 2006, 25, 2437–2448 and references cited therein.

[67] Ishikawa, T. Arkivoc 2006, vii, 148–168 and references cited therein. [68] Steiner, G.; Kopacka, H.; Ongania, K.-H.; Wurst, K.; Preishuber-Pflügl, P.; Bildstein, B. Eur. J. Inorg.

Chem. 2005, 1325–1333. [69] a) Karkhanis, D. W.; Field, L. Phosphorus Sulphur 1985, 22, 49–57. b) Marshall, C.; Ward, M. F.; Harrison,

W. T. A. J. Organomet. Chem. 2005, 690, 3970–3975. [70] Coleman, A. W.; Hitchcock, P. B.; Lappert, M. F.; Maskell, R. K.; Müller, J. H. J. Organomet. Chem. 1985,

296, 173–196. [71] Herrmann, W. A.; Köcher, C.; Gooßen, L. J.; Artus, G. R. J. Chem. Eur. J. 1996, 2, 1627–1636. [72] Schenck, T. G; Downes, J. M.; Milne, C. R. C.; Mackenzie, P. B.; Boucher, H. Whelan, J.; Bosnich, B.

Inorg. Chem. 1985, 24, 2334–2337. [73] Wehman-Ooyevaar, I. C. M.; Drenth, W.; Grove, D.; van Koten, G. Inorg. Chem. 1993, 32, 3347–3356.

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[74] Beurskens, P. T., Admiraal, G., Beurskens, G., Bosman, W. P., Garcia-Granda, S., Gould, R. O., Smits, J. M. M., Smykalla, C. (1999) The DIRDIF99 program system, Technical Report of the Crystallography Laboratory, University of Nijmegen, The Netherlands.

[75] Sheldrick, G. M. (1997). SHELXL-97. Program for crystal structure refinement. University of Göttingen, Germany.

[76] Spek, A. L. J. Appl. Cryst. 2003, 36, 7–13. [77] Otwinowski, Z.; Minor, W. Methods in Enzymology, Volume 276 (C.W. Carter, Jr. & R.M. Sweet, Eds)

Academic Press (1997) 307–326. [78] Flack, H. D. Acta Cryst. 1983, A39, 876–881.

Chapter 5

Multicomponent Approaches towards Nutlin Analogues

C–2 Functionalisation of 2H-2-Imidazolines

Robin S. Bon,a Nanda E. Sprenkels,a Manoe M. Koningstein,a Rob F. Schmitz,a Frans J. J. de Kanter,a Alexander Dömling,b Marinus B.

Groen,a Romano V.A. Orrua


bFranckensteinstrasse 9a, 81243 München, Germany

Abstract: The multicomponent synthesis of 2H-2-imidazolines has been exploited to synthesise new analogues of the p53-MDM2 interaction inhibitors called Nutlins. Alkylation and subsequent oxidation of 2H-2-imidazolines affords imidazolidine-2-ones, which can be deprotected at N–1 or N–3. Thionation and microwave assisted Liebeskind-Srogl reactions give access to 2-aryl-2-imidazolines in high overall yields.

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5.1 Introduction

In the last decades, 2-imidazoline derivatives have attracted considerable interest because of a wide variety of biological activities connected to this scaffold. Several 2-imidazolines have a high affinity for imidazoline binding sites (IBS).1 These IBS are being increasingly studied for their involvement in hypertension, regulation of blood pressure, insulin secretion control and numerous human brain disorders such as depression, neurodegeneration and opioid tolerance/dependence.2 Other targets of 2-imidazolines are estrogen receptors,3 α2-adrenoceptors,4 N-methyl-D-aspartate (NMDA) receptor channels,5 cholesterol acyltransferase,6 nicotinic acetylcholine receptors7 and serotonin receptors.8 Studies have been reported on the possible application of 2-imidazolines as, amongst others, anti-hyperglycemic,9 anti-inflammatory,10 anti-hypertensive11 and anti-hypercholesterolemic agents.6 Some typical examples of biologically active 2-imidazolines and their functions are summarised in Chart 1.

Chart 1

Recently, a series of highly substituted cis-imidazoline analogues called Nutlins (Nutley inhibitors, 9–11) has been identified as inhibitors of MDM2, a protein that negatively modulates the transcriptional activity and stability of the p53 tumour suppressor protein (Chart 2).13 The related, non-cytotoxic imidazoline 12, which contains a trans-4,5-diphenyl backbone, selectively sensitises leukaemia T cells to the chemotherapeutic agent camptothecin 13, enhancing the overall efficacy of the treatment.14

C–2 Functionalisation: Multicomponent Approaches Towards Nutlin Analogues

107

Chart 2

Although substitution patterns are diverse, it is noteworthy that most (but certainly not all) known biologically active 2-imidazolines contain a C–2 substituent. In some cases, the C–2 derivatisation even changes an agonist to an antagonist (compare 3 and 4). Nutlin compounds all contain a C–2 aryl group, which is essential for binding in the p53 pocket of MDM2.

In this Chapter, the effects of Nutlin compounds on the p53-MDM2 interaction are

explained shortly and the synthesis of known Nutlin compounds is discussed. After this, our contributions to the synthesis of 2-aryl-2-imidazolines are described. Alkylation and oxidation of 2H-2-imidazolines synthesised via our MCR (Chapters 2 and 3) and subsequent Liebeskind-Srogl coupling are the key steps in a novel methodology that provides diversely substituted Nutlin-like 2-imidazolines.

5.2 The p53 Pathway

The p53 tumour suppressor protein plays a central role in the coordination of the cellular response to stress through the initiation of growth arrest and/or the induction of apoptosis.15 The p53 gene has been the subject of intense study since it was discovered that about 50% of human cancers have mutations in this gene, and that abnormalities in this gene are among the most common molecular events correlated with neoplasia. In many cancers, the p53 pathway is inactivated indirectly through binding of viral proteins, or as a result of alterations in genes whose products interact with p53 or transmit information to or from p53 (Figure 1).

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mechanism of inactivating p53 typical tumours effect of inactivation

amino-acid-changing mutation in the DNA-binding domain

colon, breast, lung, bladder, brain, pancreas, stomach,

oesophagus and many others

prevents p53 from binding to specific DNA sequences and activating the adjacent genes

deletion of the carboxy-terminal domain

occasional tumours at many different sites

prevents the formation of tetramers of p53

multiplication of the MDM2 gene in the genome

sarcomas (cancers of connective or supportive

tissues), brain

extra MDM2 stimulates the degradation of p53

viral infection cervix, liver, lymphomas

(cancers in lymphocytes or histiocytes)

products of viral oncogenes bind to and inactivate p53 in

the cell, in some cases stimulating p53 degradation

deletion of the p14ARF gene breast, brain, lung and

others, especially when p53 itself is not mutated

failure to inhibit MDM2 and keep p53 degradation under

control

mislocation of p53 to the cytoplasm, outside the nucleus

breast, neuroblastomas lack of p53 function (p53

functions only in the nucleus)

Figure 1. The many ways in which p53 may malfunction in human cancers

In a normal cell, the p53 network is ‘off’. The amount of p53 protein in cells is determined mainly by the rate at which it is degraded, rather than by the rate at which it is made. Degradation of p53 protein proceeds through ubiquitin-mediated proteolysis.16 One of the enzymes involved in labelling p53 with ubiquitin is MDM2.12 The amounts of p53 and MDM2 proteins in the cell are controlled by a feedback loop (Figure 2). The p53 protein binds to the regulatory region of the MDM2 gene and stimulates the transmission of this gene into messenger RNA, which is translated into MDM2 protein. This protein binds to p53 and stimulates the addition of ubiquitin groups to the C-terminus of p53, which is then degraded. Furthermore, binding of MDM2 inhibits the transcriptional abilities of p53 and MDM2 is also involved in the nuclear export of p53. These three effects lower the concentration of p53 and reduce transcription of the MDM2 gene, closing the feedback loop and allowing p53 levels to rise again.

The p53 network is activated only when cells are stressed or damaged. Such cells pose a

threat to the organism because they are more likely than normal cells to contain mutations and exhibit abnormal cell-cycle control. Therefore, they present a greater risk to become cancerous. The existence of at least three pathways by which the p53 network can be activated has been confirmed. These pathways are triggered by, for example, DNA damage, the expression of oncogenes (cell-cycle accelerators) and a wide range of chemotherapeutic drugs. All three pathways inhibit the degradation of p53 protein, thus stabilising p53 at a


109

high concentration. This p53 undergoes conformational changes resulting from modifications such as addition or removal of phosphate, acetyl, glycosyl, ribose, ubiquitin or ‘sumo’ groups (sumo is a ubiquitin-like polypeptide that can reversibly modify proteins). The conformational changes allow p53 to become a transcriptional activator. The p53 protein binds to a particular DNA sequence and activates the expression (transcription) of adjacent genes. Expression of these genes can lead to a variety of processes, such as cell cycle arrest, apoptosis, repair of damaged DNA or the inhibition of blood vessel formation (which reduces the transport of nutrients needed for tumour growth). Finally, p53 may cause cell death by directly stimulating mitochondria to produce an excess of highly toxic reactive oxygen species.

Figure 2. Simplified representation of the p53 network

5.3 Nutlins as Novel Anti-Cancer Drugs

About 50% of human tumours contain the wild-type p53 protein. Many of these cancers have elevated level of MDM2 resulting from overexpression of the MDM2 gene, causing inhibition of the p53 pathway. Reactivation of the p53 pathway through the inhibition of MDM2 has been proposed as a novel therapeutic strategy to suppress tumour growth.17

Several studies have shown that disruption of the p53-MDM2 interaction by

macromolecular approaches or by the suppression of MDM2 expression can lead to the activation of p53 and tumour growth inhibition.18 Recently, small-molecule MDM2 antagonists have been reported that inhibit the p53-MDM2 interaction. 13,17,19 The Nutlins 9–11, which were discovered in Nutley, New Jersey, have shown to displace recombinant

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p53 protein from its complex with MDM2 with median inhibitory concentration (IC50) values in the 100 to 300 nM range.13 The activity of the most active enantiomer of Nutlin-3 is only 18-fold lower than that of the best peptide ligand known, which is not common for such a small compound.17,20 A great advantage of these compounds is that they are suitable for oral administration. Both in vitro and in vivo tests show that Nutlins only display their anti-tumour activity in cells containing wild-type p53, and not in cells lacking p53 or cells containing mutant p53.13 This led to the conclusion that Nutlins reactivate the p53 pathway by blocking the p53-MDM2 interaction. Treatment of mice bearing tumours with Nutlin-3 (11) led to 90% inhibition of tumour growth, while normal cells were able to function even after 34 days of medication. This suggests that normal tissues have higher tolerance to p53 than cancer tissues.

Nutlins are not only useful for the treatment of cancers that result from the

overexpression of MDM2. Also the growth of tumours containing mutant p53 can be stopped using a combination of Nutlins and Paclitaxel.21 Paclitaxel is a mitotic inhibitor that is used in antimitotic chemotherapy against p53-deficient tumours. It disrupts cells that are in the mitotic phase (M) of the cell cycle. Cells in the G1 or G2 phase, which are the phases right after and just before cell division (mitosis), respectively, are protected from the cytotoxicity of mitotic inhibitors.

At the cellular level, inhibition of the p53-MDM2 interaction by Nutlins leads to cell

cycle arrest in the G1 or G2 phase. This only occurs in cells containing wild-type p53; the cell cycle of cells with mutant p53 is not affected. Therefore, administration of Nutlins protects normal cells from mitotic block induced by Paclitaxel, which is followed by apoptosis, while in the cancer cells, apoptosis is induced. After treatment with Paclitaxel, administration of Nutlins is stopped, after which the normal cells continue their normal cell cycle.

A. Normal cell (wild-type p53)

B. Cancer cell (mutant p53)

Figure 3. Selective protection of normal cells from Paclitaxel cytotoxicity by Nutlins


111

5.4 Interaction of Nutlins and MDM2

Only residues 15 to 29 of p53 are responsible for binding MDM2.22 The crystal structure of the MDM2-Nutlin-2 complex shows that the Nutlin mimics the interactions of the p53 peptide with MDM2 to a high degree.13 One bromophenyl moiety is located deeply in the Trp pocket, the other occupies the Leu pocket and the ethyl ether side chain is directed towards the Phe pocket. In essence, the 2-imidazoline core acts as a fairly rigid replacement of the helical backbone of the p53 peptide and directs its substituents in the pockets normally occupied by Phe19, Trp23 and Leu26 of p53.

A buffered solution of a complex of Nutlin 14 and MDM2 has been studied using NMR

spectroscopy.23 It was shown that the chlorophenyl groups and the isopropyl ether of 14 occupy the same hydrophobic pockets as the p53 protein. The location of the N–1 substituent could not be determined. Furthermore, it was determined that the overall structure of Nutlin 14-bound MDM2 is quite similar to that of p53-bound MDM2.

N

N

Cl

Cl

14

ON NH

O

O

Computational studies on the Nutlin-MDM2 interaction suggest that the inhibition of MDM2 by Nutlin compounds can possibly be improved changing the aromatic ring that occupies the Trp23 pocket, to a indolyl group and by using a bigger N–1 substituent.24

5.5 Synthesis of Nutlins and Nutlin Analogues

Nutlins can be prepared as illustrated in Scheme 1.23 Bromination and subsequent alkylation of 3-methoxyphenol 15 gives 1-bromo-2-isopropoxy-4-methoxybenzene 17. Palladium catalysed cyanation and treatment of the resulting cyanide with hydrogen chloride in ethanol gives imidate 18, which can be condensed with meso-1,2-di(4-chlorophenyl)ethane-1,2-diamine 19 to provide cis-imidazoline intermediate 20. Treatment of 20 with phosgene and reaction of the resulting carbamoyl chloride affords, after acidic workup, Nutlin compound 14 as hydrochloride salt in 6% overall yield.

The key step in this synthetic route is the condensation of a diamine with an imidate.

Although this reaction works rather well, quick variation of the substituents is difficult, because the availability of 1,2-phenylethane-1,2-diamines is rather limited. Most commercially available ethanediamines are symmetrical, giving access to Nutlins containing equal C–4 and C–5 substituents. Furthermore, 1H-2-imidazolines (like 20) exist as a

Chapter 5

112

mixture of tautomers. Therefore, the carbamoylation of unsymmetrical 1H-2-imidazolines (with different C–4 and C–5 substituents) would lead to a mixture of two regioisomers.

Scheme 1

Another approach is the diastereoselective, trimethylsilyl chloride mediated MCR between oxazolones 22, aldehydes and amines, which affords C–2 functionalised 2-imidazolines 23 (Scheme 2).25 In this reaction, the diastereochemical outcome is determined by the R1 and R2 substituents. Biological evaluation of a library of imidazolines 23 resulted in the discovery of imidazoline 12 as an enhancer of the chemotherapeutic efficacy of anticancer agents.14 However, Nutlins require two cis-oriented, hydrophobic C–4 and C–5 substituents in combination with an aromatic group at C–2. Since the application of oxazolones with an aromatic R1 group leads to almost exclusive formation of imidazolines with trans oriented R2 and R3 groups (cis-23), this method seems less efficient for the synthesis of Nutlin analogues.

Scheme 2

Our versatile multicomponent synthesis involving amines 26, aldehydes 27 and isocyanoacetates 28 (Chapter 2) gives access to 2H-2-imidazolines.26 The R1 and R2 substituents can be varied easily by the choice of readily available amines and aldehydes. Furthermore, the reaction is generally diastereoselective in favour of the 4,5-trans-


113

imidazolines (so R2 and R3 are cis, like in Nutlins). Therefore, we propose to exploit this method to synthesise libraries of new, Nutlin-like p53-MDM2 interaction inhibitors containing a carboxylate that might serve to enhance water solubility. In order to arrive at the required substitution pattern, 2H-2-imidazolines 25 resulting from the cycloaddition between isocyanoacetates and in situ generated imines should be arylated at the C–2 position. In the following paragraphs, initial studies towards the synthesis of Nutlin analogues, based on the multicomponent synthesis of 2H-2-imidazolines, are presented.

Scheme 3

5.6 Multicomponent Synthesis of 2H-2-Imidazolines

Nutlins always contain para-halogenated phenyl rings that are crucial for the interaction with the Trp23 and Leu26 pockets of MDM2. Thus, for the envisioned synthetic route (Scheme 3) 2-(p-halophenyl)-2-isocyanoacetates are needed. Isocyanoacetate 32, containing a para-chlorophenyl group, was synthesised from p-chlorophenylglycine 29 according to established procedures. Esterification and formylation of 29 gives formamide 31 in almost quantitative yield. Although dehydration of 31 is possible with POCl3/Et3N, the use of triphosgene/NMM gives a cleaner reaction and higher yield in this case.

Scheme 4a

a Reagents and conditions: (a) 1. SOCl2, MeOH, reflux, 2 h; 2. NaHCO3 (sat), EtOAc, rt, 10 min. (b) ethyl formate, pTSA,

reflux, 18 h. (3) triphosgene, NMM, DCM, −30 ºC to −5 ºC, 4 h.

Employing isocyanoacetate 32 in MCRs with amines and aldehydes provides 2H-2-imidazolines in high yields and in most cases, the formation of the preferred trans isomers is favoured over formation of the cis isomers (Table 1).27 The use of p-chlorobenzaldehyde 34 leads to the 4,5-di(p-chlorophenyl) backbone found in Nutlins 1 and 3 (entries 1 and 2), while protected indole-3-carboxaldehyde 38 affords imidazolines containing a 5-indolyl substituent which might improve binding to the Trp23 domain of MDM2 (entries 3 and 4).23

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114

Table 1. Multicomponent synthesis of 4-(p-chlorophenyl)-2H-2-imidazolinesa entry amine aldehyde imidazoline yield (dr)b

1c

NH2

OMe

33

Cl

O34 N

NP CP

P CP 35

PMB

MeO2C

85% (71:29)

2c NH2

36

Cl

O34 N

NPCP

PCP 37Me O2C

81% (74:26)

3c

NH2

OMe

33

N

O

Boc

38 N

N

P CP 39

PMB

MeO2C

NBoc

76% (42:58)

4d NH2

36

N

O

Boc

38 N

N

P CP 40MeO2C

NBoc

84% (76:24)

a Alle reactions were performed with 32 as the isocyanide component. b Isolated yields are reported. Diastereomeric ratios were calculated from 1H NMR spectra. c Conditions: Na2SO4, DCM, rt, 18 h. d Conditions: Na2SO4, MeOH, rt, 18 h. PMB = p-methoxybenzyl, PCP = p-chlorophenyl, Boc = tert-butyloxycarbonyl.

Initial studies in our group have shown that direct C–2 functionalisation of

2H-2-imidazolines using rhodium28 or palladium29 catalysis is not straightforward.30 Furthermore, the imidazolines from Table 1 decomposed under the harsh reaction conditions necessary for rhodium catalysed C–C couplings (>150 ºC, microwave irradiation).30a Thus, a mild procedure for the selective C–2 arylation of 2H-2-imidazolines containing halogenated phenyl groups had to be developed.

5.7 Oxidations of 2H-2-Imidazolinium Salts

Recently, Liebeskind and Srogl reported the Pd(0) catalysed, Cu(I) mediated coupling of thioether-type species with boronic acids under neutral conditions.31 The high thiophilicity of the soft Cu(I) carboxylate cofactor facilitates selective C–C coupling with isothioureas even in the presence of a Suzuki-active bromide.32 Kappe et al. used this elegant procedure to directly arylate 3,4-dihydropyrimidine-2-thiones under microwave irradiation, leading to the quick generation of small libraries of analogues of hepatitis B virus replication inhibitors.33


115

Scheme 5

We envisioned the mild and easy sulfoxidation of 2H-2-imidazolinium salts through the reaction of in situ generated N-heterocyclic carbenes with elemental sulfur (Chapter 4) as an appropriate method to synthesise precursors for Liebeskind-Srogl reactions (Scheme 5). Strategic choice of R1 and R3 groups should allow selective deprotection of the resulting imidazolidin-2-thiones 43 or 45, leading to Nutlin analogues with either a 4-carboxylate (44) or a 5-carboxylate (46).

Scheme 6a

a Reagents and conditions: (a) MeI, DCM, rt, 18 h. (b) KOtBu, S8, THF, rt, 2 h.

Methylation and sulfoxidation of imidazoline 35 affords the cyclic thioureas 48a and 48b, which can be separated using flash column chromatography, in good (but unoptimised) yield (Scheme 6). However, cleavage of the p-methoxybenzyl group from N–1 could not be realised. Both oxidative and acidic conditions give decomposition of the starting material, probably because of the sensitive sulfur group (Scheme 7).

Scheme 7a

a Reagents and conditions: (a) CAN, MeCN, H2O, rt, 2 h.. (b) TFA, 80 ºC (microwave), 30 min. (c) TFA, rt, 18 h.

Currently, we are searching for other protective groups that are compatible with the alkylation/sulfoxidation procedure and cleavable from the resulting thioureas under mild conditions.

Chapter 5

116

Scheme 8

Another route towards cyclic thioureas like 43 and 45, the Liebeskind-Srogl precursors, was considered as well. Several research groups have reported the preparation of imidazolidin-2-thiones 50 by the thionation of imidazolidin-2-ones 51 using Lawesson’s reagent 53,34 the superior reagent for the conversion of carbonyls to thiocarbonyls (

Scheme 8).35 However, to apply this route in the sythesis of imidazolidin-2-thiones from imidazolines, a method for the oxidation of imidazolines was required.

Scheme 9a

a Reagents and conditions: (a) mCPBA, DCM, rt, 18 h. (b) MeI, DCM, rt, 18 h. (c) mCPBA, DCM, rt, 18 h.

Although (low-yielding) oxidations of benzimidazoles with mCPBA are known,36 this procedure does not lead to the direct oxidation of imidazoline 54, which we used as a model system (Scheme 9). In contrast, the oxidation of imidazolinium salt 56 with mCPBA in DCM proceeded smoothly, affording imidazolidin-2-one 57 in reasonable yield.

Scheme 10a

a Reagents and conditions: (a) mCPBA, DCM, 0 ºC to rt, 18 h. (b) TFA, reflux, 1 h. (c) Lawesson’s reagent, toluene, reflux, 18 h.

Thus, oxidation of imidazolinium iodide 47 affords cyclic urea 58a and 58b, which could be separated using flash column chromatography, in a combined yield of 82% (Scheme 10). For a clean reaction it proved important to add the mCPBA to a cooled solution of the salt


117

47. Acidic cleavage of the PMB group and subsequent thionation provides the Liebeskind-Srogl precursors 49a and 49b with a C–5 ester function in very high yields.

With the above decscribed methodology available, we now turned to the synthesis of

Liebeskind-Srogl precursors containing the ester functionality at C–4. Clean p-methoxybenzylation of imidazoline 37 can be achieved under Finkelstein conditions in quantitative yield (Scheme 11). Oxidation of the imidazolinium salt gives cyclic urea 61 in reasonable yield. Unlike for 58, separation of the two diasteromers of 61 proved very difficult. Therefore, we decided to pursue our synthetic route with the diastereomeric mixture. Deprotection and subsequent thionation of 61 both proceed in excellent yield, affording the desired 3H-imidazolidin-2-thione 63. It must be noted that small variations in diastereomeric ratios can be attributed to minor losses of material during flash column chromatography.

Scheme 11a

a Reagents and conditions: (a) PMBBr, NaI, acetone, 18 h. (b) mCPBA, DCM, 0 ºC to rt, 18 h. (c) TFA, reflux, 1 h. (d) Lawesson’s

reagent, toluene, reflux, 18 h.

5.8 Liebeskind-Srogl Couplings under Microwave Irradiation

Applying controlled single-mode microwave heating in sealed vessels, reaction conditions for the Liebeskind-Srogl reactions were refined with respect to the solvent. Initially, coupling reactions between boronic acids and imidazolidin-2-thiones were performed under conditions reported by Kappe et al. (PhB(OH)2, Pd(PPh3)4, CuTC, THF, microwave, 100 ºC, 30 min.).33 However, this procedure afforded only traces of the desired products. The reactions proceed much better in DMF, as reported for 2-methylthioimidazolones.37

As shown in Table 2, both reaction time and temperature are important for achieving a

good conversion of imidazolidin-2-thione 63 to 2-aryl-2-imidazolines 64 and 65. Although

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118

the reaction conditions are not completely optimised yet, it is evident that the selective C–2 arylation of cyclic thiourea at 130 ºC affords the desired Nutlin analogues in reasonable yield.

Table 2. Liebeskind-Srogl reactions under microwave radiation

entry Ar T (ºC) t (min) product yield (%)a yield cfsm (%)b trans:cisc 1 Ph 100 60 64 34 38 76:24 2 Ph 130 30 64 51 60 79:21 3 Ph 130 60 64 65 65 75:25 4 PMP 100 60 65 6 30 75:25 5 PMP 130 60 65 55 63 75:25 a Isolated yields. b Yields corrected for recovered starting material. c Isolated diastereomeric ratios. PCP =

p-chlorophenyl, CuTC = copper(I) thiophene-2-carboxylate, PMP = p-methoxyphenyl.

Also imidazolidin-2-thione 49b was subjected to microwave mediated arylations (Table 3).

Again, reaction time and temperature appear crucial. At 130 ºC, reaction with phenyl boronic acid for 60 minutes gave 2-aryl-2-imidazoline 66 in moderate yield (entry 3).

Table 3. Liebeskind-Srogl reactions under microwave radiation

entry Ar T (ºC) t (min) product yield (%)a yield cfsm (%)b 1 Ph 100 60 66 14 16 2 Ph 130 30 66 46 46 3 Ph 130 60 66 51 52 4 PMP 100 45 67 24 29 5 PMP 100 60 67 30 35 6 PMP 130 60 67 41 43 a Isolated yields. b Yields corrected for recovered starting material. PCP = p-chlorophenyl,

CuTC = copper(I) thiophenecarboxylate, PMP = p-methoxyphenyl.


119

Arylation of 49b with p-methoxyphenyl boronic acid was only performed in 41% yield so far (entry 6). As soon as new batches of 49 are available again, both C–C coupling reactions should be further optimised.

5.9 Conclusions

The p53 tumour suppressor is an important transcription factor that protects cells from malignant transformations. Most human cancers have a defect in the p53 pathway, either because of mutations in the p53 gene, or because of overexpression of its natural inhibitor, MDM2. Recently discovered inhibitors of the p53-MDM2 interaction called Nutlins reactivate the p53 pathway and therefore form a potent new class of anti-tumour agents. In our group, a versatile route towards Nutlin analogues has been developed. A MCR from amines, aldehydes and 2-(p-chlorophenyl)-2-isocyanoacetate 32 gives access to 2H-2-imidazolines containing Nutlin-like backbones. However, like many biologically active 2-imidazolines, Nutlins contain a C–2 substituent. C–2 arylation of 2H-imidazolines can be achieved in 5 steps under mild conditions. The key steps involve the oxidation of 2H-2-imidazolinium salts and the Liebeskind-Srogl coupling of cyclic tioureas with boronic acids. Nutlin analogues containing either a C–4 carboxylic ester (64 and 65) or a C–5 carboxylic ester (66 and 67) have been prepared in yields ranging from 18% to 28% over 9 steps, starting from p-chlorophenylglycine 29. Although the reaction conditions for the Liebeskind-Srogl couplings need further optimisation, the high overall yields and the flexibility with respect to the substitution pattern make this procedure applicable for the generation of new libraries of possible p53-MDM2 interaction inhibitors. Finally, the choice of appropriate protective groups that are easily cleavable from imidazolidin-2-thiones may even shorten the route by one step.


Dr. Marek Smoluch (Vrije Universiteit Amsterdam) is gratefully acknowledged for conducting (HR)MS measurements.


General Information: All reactions were carried out under atmospheric conditions, unless stated otherwise. Standard syringe techniques were applied for transfer of air sensitive reagents and dry solvents. Melting points were measured using a Stuart Scientific SMP3 melting point apparatus and are uncorrected. Infrared (IR) spectra were obtained from CHCl3 films on NaCl tablets (unless noted otherwise), using a Matteson Instuments 6030 Galaxy Series FT-IR spectrophotometer and wavelengths (ν) are reported in cm−1. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 (400.13 MHz and 100.61 MHz respectively) or a Bruker Avance 250 (250.13 MHz and 62.90 MHz respectively) with chemical shifts (δ) reported in ppm downfield from tetramethylsilane. MS and HRMS spectra data were recorded on a Finnigan Mat 900 spectrometer or in the Laboratory of Organic Chemistry of the Wageningen University (NL) on a Finnigan MAT95 spectrometer. Chromatographic purification refers to flash chromatography using the indicated solvent (mixture) and Baker 7024-02 silica gel (40μ, 60 Å). Thin Layer Chromatography was performed using silica plates from Merck

Chapter 5

120

(Kieselgel 60 F254 on aluminium with fluorescence indicator. Compounds on TLC were visualised by UV-detection unless stated otherwise. THF was dried and distilled from sodium benzophenone ketyl prior to use. DCM was dried and distilled from CaH2 prior to use. Toluene was distilled from sodium prior to use. DMF was dreid and distilled from phenylzinc iodide prior to use. Other commercially available reagents were used as purchased. Microwave Experiments: Microwave-assisted reactions were performed in a Discover (CEM Corporation) single-mode microwave instrument producing controlled irradiation at 2450 MHz, using standard sealed microwave glass vials. Reaction temperatures were monitored with an IR sensor on the outside wall of the reaction vials. Reaction times refer to hold times at the indicated temperatures, not to total irradiation times.

1-(4-Chlorophenyl)-2-methoxy-2-oxoethanaminium chloride. p-Chlorophenylglycine (8.62g, 46.5mmol) was dissolved in MeOH (110 mL). The solution was cooled to 0˚ C and thionyl chloride (6.8 mL, 93 mmol) was added drop wise. The reaction mixture was heated under reflux for 3 h. Cooling to rt followed by concentration in vacuo afforded the title compound as a white solid (10.98 g, quant.) 1H NMR (250 MHz, D2O) δ (ppm) 7.54 (d, J =

8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 5.30 (s, 1H), 3.82 (s, 3H).

Methyl 2-amino-2-(4-chlorophenyl)acetate 30. 1-(4-Chlorophenyl)-2-methoxy-2-oxoethanaminium chloride (3.33 g, 14.1 mmol) was suspended in EtOAc (100 mL). Saturated NaHCO3 (aq) (80 mL) was added and the suspension was stirred until the organic layer was clear and slightly orange. The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine and dried with Na2SO4. Filtration

and concentration in vacuo afforded 30 as a yellow/orange solid (2.79 g, 99%) 1H NMR (250 MHz, CDCl3) δ (ppm) 7.36 (s, 4H), 4.67 (s, 1H), 3.73 (s, 3H), 2.60 (br s, 2H).

Methyl 2-(4-chlorophenyl)-2-formamidoacetate 31. Methyl 2-amino-2-(4-chlorophenyl)acetate 30 (2.79 g, 14.0 mmol) was dissolved in ethyl formate (80 mL) and a small crystal of pTSA was added. The reaction mixture was refluxed overnight, cooled to rt and the solvent was evaporated. The product was dissolved in DCM, washed with water, dried with Na2SO4, and concentrated in vacuo to afford 31 as a yellow solid (3.15 g, 99%) 1H NMR (200

MHz, CDCl3) δ (ppm) 8.22 (s, 1H), 7.31 (s, 4H), 6.86 (br s, 1H), 5.62 (d, J = 7.2 Hz, 1H), 3.72 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 176.6 (C), 170.6 (C), 160.5 (CH), 134.6 (C), 129.2 (2×CH), 129.0 (2×CH), 54.4 (CH3), 53.2 (CH); HRMS (EI, 70eV) calculated for C10H10ClNO3 (M+) 227.0349, found 227.0346.

Methyl 2-(4-chlorophenyl)-2-isocyanoacetate 32. This reaction was carried out under an inert atmosphere of dry nitrogen. Methyl 2-(4-chlorophenyl)-2-formamidoacetate 31 (910 mg, 4.0 mmol) was dissolved in DCM (10 mL) and cooled to −30˚C. Triphosgene (504 mg, 1.7 mmol) and N-methyl morpholine (1.57 mL, 14.3 mmol) were added slowly. The solution turned darker orange and after 30 minutes at −30˚C, the temperature was raised to −5˚C and kept at this temperature for

an additional 3 hours, during which the solution slowly turned darker. The reaction mixture was quenched in 20 mL of icewater. The layers were separated, and the aqueous layer was extracted with Et2O. The organic layers were combined, washed with brine and dried with Na2SO4. Concentration in vacuo followed by flash column chromatography (cyclohexane:ethyl acetate = 4:1), afforded 32 as an orange oil (640 mg, 77%). 1H NMR (250 MHz, CDCl3) δ (ppm) 7.42 (br s, 4H), 5.35 (s, 1H), 3.80 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 165.6 (C), 162.2 (C), 135.8 (C), 130.2 (C), 129.4 (2×CH), 128.0 (2×CH), 59.6 (C), 53.9 (CH3); IR (neat) 2954 (m), 2148 (s), 1753 (s), 1493 (s), 1435 (m), 1250 (m), 1211 (m), 1092 (s), 1014 (s); HRMS (EI, 70eV) calculated for C10H8ClNO2 (M+) 209.0244, found 209.0248.

NH3+MeO2C

Cl

Cl−

NH2MeO2C

Cl

NH

MeO2C

Cl

O

NCMeO2C

Cl


121

General Procedure I for the Synthesis of 2-Imidazolines: Reactions were carried out under an inert atmosphere of dry nitrogen at a concentration of 1 M of amine, 1 M of aldehyde and 0.5 M of isocyanide in dry DCM or MeOH. Na2SO4 and the aldehyde were added, at rt, to a stirred solution of the amine. After the mixture was stirred for 2 h, the isocyanide was added and the reaction mixture was stirred at rt for an additional 18 h. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (c-hexane:EtOAc:Et3N = 2:1:0.01, gradient, unless stated otherwise).

Methyl 4,5-bis(4-chlorophenyl)-1-(4-methoxybenzyl)-4,5-dihydro-1H-imidazole-4-carboxylate 35. According to General Procedure I, reaction between p-methoxybenzylamine 33 (2.74 g, 20 mmol), p-chlorobenzaldehyde 34 (2.80 g, 20.0 mmol) and isocyanoacetate 32 (2.07 g,

9.9 mmol) in DCM, followed by column chromatography (EtOAc:Et3N = 1:0.01), afforded 35 (3.96 g, 85%) as a 71:29 mixture of diastereomers as a yellow solid. 1H NMR (250 MHz, CDCl3) δ (ppm) 7.47 (d, J = 43.0 Hz, 1H), 7.36–7.21 (m, 3H + 4H), 7.10–6.98 (m, 4H + 4H), 6.89–6.76 (m, 5H + 5H), 5.28 (s, 1H), 4.64 (s, 1H), 4.36–4.31 (m, 1H + 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.83–3.74 (m, 4H + 1H), 3.28 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 173.5 (C), 170.6 (C), 159.4 (C), 156.7 (CH), 155.9 (CH), 141.6 (C), 135.9 (C), 134.9 (C), 134.4 (C), 133.7 (2×C), 133.6 (2×C), 133.2 (C), 120.0 (2×CH), 129.4 (2×CH), 129.3 (2×CH), 129.0 (2×CH), 128.8 (2×CH), 128.3 (2×CH), 128.2 (2×CH), 128.08 (2×CH), 128.06 (2×CH), 127.8 (2×CH), 127.1 (C), 126.9 (C), 114.1 (2×CH), 114.2 (2×CH), 84.7 (C), 83.8 (C), 72.4 (CH3), 68.5 (CH3), 55.1 (CH3 + CH3), 53.1 (CH), 52.1 (CH), 48.6 (CH2), 48.1 (CH2); IR (neat) 1730 (s), 1602 (s); HRMS (EI, 70 eV) calculated for C25H22Cl2N2O3 (M+) 468.1007, found 468.1002.

Methyl 1-butyl-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazole-4-carboxylate 37. According to General Procedure I, reaction between n-butylamine 36 (730 mg, 10.0 mmol), p-chlorobenzaldehyde 34 (1.40 g, 10.0 mmol) and isocyanoacetate 32 (990 mg, 4.74 mmol) in DCM, followed by column chromatography (EtOAc:Et3N = 1:0.01), afforded 37 (1.61 g,

84%) as a 74:26 mixture of diastereomers as a pale yellow oil. 1H NMR (250 MHz, CDCl3) δ (ppm) 7.69 (d, J = 8.7 Hz, 2H), 7.39–7.34 (m, 4H), 7.30–7.26 (m, 3H + 1H), 7.05–7.01 (m, 2H + 2H), 6.90–6.86 (m, 2H + 2H), 5.51 (s, 1H), 4.81 (s, 1H), 3.77 (s, 3H), 3.28 (s, 3H), 3.20–3.08 (m, 1H + 1H), 2.89–2.78 (m, 1H + 1H), 1.54–1.13 (m, 4H + 4H), 0.92–0.79 (m, 3H + 3H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 173.8 (C), 170.6 (C), 156.8 (CH), 156.1 (CH), 141.9 (C), 136.1 (C), 135.2 (C), 134.4 (C), 134.0 (C), 133.6 (C), 133.5 (C), 133.1 (C), 129.8 (2×CH), 129.2 (2×CH), 128.8 (2×CH), 128.4 (2×CH), 128.17 (2×CH), 128.15 (2×CH), 128.08 (2×CH), 127.8 (2×CH), 84.65 (C), 83.9 (C), 73.5 (CH3), 68.7 (CH3), 53.1 (CH), 52.1 (CH), 44.8 (CH2), 44.5 (CH2), 30.2 (CH2), 30.0 (CH2), 19.8 (CH2), 19.7 (CH2), 13.6 (CH3), 13.5 (CH3); IR (neat) 1729 (s), 1599 (s); HRMS (EI, 70 eV) calculated for C21H22Cl2N2O2 (M+) 404.1058, found 404.1046.

tert-Butyl 3-(4-(4-chlorophenyl)-1-(4-methoxybenzyl)-4-(methoxycarbonyl)-4,5-dihydro-1H-imidazol-5-yl)-1H-indole-1-carboxylate 39. According to General Procedure I, reaction between p-methoxybenzylamine 33 (384 mg, 2.8 mmol), N-Boc-indolecarboxaldehyde 38 (690 mg, 2.8 mmol) and isocyanoacetate 32 (419 mg, 2.0 mmol) in DCM, followed by column chromatography, afforded 39 (364 mg, 76%) as a 42:58 mixture

of diastereomers as an orange/pink solid. 1H NMR (400 MHz, DMSO-d6, 360 K): δ (ppm) 8.09 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.61–7.56 (m, 3H + 3H), 7.54 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.38–7.32 (m, 2H + 2H), 7.25–7.20 (m, 1H + 1H), 7.09–7.01 (m, 1H), 7.03 (d, J = 8.6 Hz, 2H), 6.97 (br s, 1H + 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 8.7 Hz, 2H), 5.58 (s, 1H), 4.99 (s, 1H), 4.46 (d, J = 15.1 Hz, 1H), 4.39 (d, J = 14.9 Hz, 1H), 3.86–3.82 (m, 1H + 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.64 (s, 3H), 3.07 (s, 3H), 1.67 (s, 9H), 1.59 (s, 9H); 13C NMR (100.6 MHz, DMSO-d6, 360 K) δ (ppm) 172.5 (C), 170.2 (C), 158.4 (C), 158.3 (C), 156.8 (CH), 156.1 (CH), 148.5 (C), 148.2 (C), 142.2 (C + C), 137.3 (C + C), 134.8 (C + C), 131.7 (C), 131.2 (C), 128.72 (4×CH), 128.67 (4×CH), 128.3 (CH), 128.1 (C + C), 128.1 (2×CH), 127.4 (2×CH), 126.4 (CH), 125.4 (CH), 124.0 (CH), 123.6 (CH), 122.0 (CH), 121.8 (CH), 119.6 (CH), 119.4 (C), 115.8 (C), 114.3 (CH),

N

N

PCP

PCPMeO2C

PMB

N

N

PCP

PCPMeO2C

N

N

PCPMeO2C

PMBNBoc

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122

114.0 (CH), 113.54 (2×CH), 113.46 (2×CH), 83.8 (C + C), 83.4 (C + C), 65.1 (CH), 61.4 (CH), 54.8 (CH3), 54.7 (CH3), 52.0 (CH3), 50.8 (CH3), 47.5 (CH2), 47.3 (CH2), 27.4 (3×CH3), 27.3 (3×CH3); IR (KBr) 1733 (s), 1599 (s), 1512 (s), 1452 (s), 1370 (s), 1248 (s), 1153 (s), 1089 (s); HRMS (EI, 70 eV) calculated for C32H32ClN3O5 (M+) 573.2030, found 573.2036.

tert-Butyl 3-(1-butyl-4-(4-chlorophenyl)-4-(methoxycarbonyl)-4,5-dihydro-1H-imidazol-5-yl)-1H-indole-1-carboxylate 40. According to General Procedure I, reaction between n-butylamine 36 (1.10 g, 15.0 mmol), N-Boc-indolecarboxaldehyde 38 (3.68 g, 15.0 mmol) and isocyanoacetate 32 (2.89 g, 13.8 mmol) in MeOH, followed by column chromatography, afforded 40 (5.9 g, 84%) as a 76:24 mixture of diastereomers as a pale

yellow solid. 1H NMR (400 MHz, CDCl3, 328 K) δ (ppm) 8.14 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.35–6.99 (m, 6H + 5H), 6.88 (d, J = 8.3 Hz, 2H + 2H), 5.83 (s, 1H), 5.04 (s, 1H), 3.74 (s, 3H), 3.16 (s, 3H), 3.13–3.04 (m, 1H + 1H), 2.90–2.84 (m, 1H + 1H), 1.69 (s, 9H), 1.63 (s, 9H), 1.52–1.45 (m, 2H), 1.37–1.12 (m, 2H + 4H), 0.85 (t, J = 7.3 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ (ppm) 174.0 (C), 156.4 (CH), 156.1 (CH), 149.4 (C), 149.3 (C), 136.9 (2×C), 133.6 (C), 128.1 (3×CH + 5×CH), 127.3 (2×CH), 125.5 (CH), 124.1 (CH + CH), 122.7 (CH + CH), 120.1 (CH), 115.6 (C), 115.3 (CH), 114.9 (CH), 84.3 (C), 83.9 (C), 67.9 (CH), 62.6 (CH), 53.2 (CH3), 52.1 (CH3), 44.8 (CH2), 44.3 (CH2), 30.3 (CH2), 30.2 (CH2), 28.2 (3×CH3), 28.1 (3×CH3), 19.8 (CH2), 19.7 (CH2), 13.6 (CH3), 13.5 (CH3); the aliphatic CH signals could only be found with gs-HSQC measurements at 328 K); the quaternary carbons of the minor diastereomer of 40 could not be detected; IR (KBr) 2957 (s), 1734 (s), 1599 (s), 1570 (m), 1452 (s), 1370 (s), 1257 (s), 1155 (s), 1089 (s); HRMS (EI, 70 eV) calculated for C28H32ClN3O4 (M+) 509.2081, found 509.2082.

4,5-Bis(4-chlorophenyl)-1-(4-methoxybenzyl)-4-(methoxycarbonyl)-3-methyl-4,5-dihydro-1H-imidazolium iodide 47. Methyl iodide (447 mg, 3.15 mmol) was added to a solution of imidazoline 35 (1.408 g, 3 mmol) in DCM (20 mL). The reaction mixture was stirred at rt for 18 h and concentrated in vacuo to afford 47 (1.83 g, quant.) as a 68:32 mixture of diastereomers as a

pale yellow solid. 1H NMR (250 MHz, CDCl3) δ (ppm) 10.65 (s, 1H), 10.52 (s, 1H), 7.48–7.29 (m, 4H + 2H), 7.20–7.17 (m, 4H + 6H), 7.01–6.91 (m, 2H + 2H), 6.91–6.83 (m, 2H + 2H), 5.73 (s, 1H), 5.45 (d, J = 14.1 Hz, 1H), 5.31 (d, J = 14.4 Hz, 1H), 5.14 (s, 1H), 4.23–4.13 (m, 1H + 1H), 3.96 (s, 3H), 3.80 (s, 3H + 3H), 3.56 (s, 3H), 3.34 (s, 3H), 3.26 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 168.9 (C), 165.8 (C), 160.5 (C), 160.2 (C), 160.1 (CH), 158.4 (CH), 136.9 (2×C), 135.8 (C), 135.6 (C), 132.9 (C), 131.3 (2×CH), 131.0 (4×CH), 130.5 (2×CH), 130.0 (2×CH), 129.9 (C), 129.8 (2×CH), 129.3 (2×CH), 129.1 (2×CH), 128.9 (2×CH), 128.88 (2×CH), 128.84 (C), 123.4 (2×C), 123.1 (C), 114.7 (2×CH), 114.6 (2×CH), 80.6 (C), 80.2 (C), 74.1 (CH3), 70.2 (CH3), 55.4 (2×CH3), 54.6 (CH), 53.2 (CH), 50.5 (CH2), 50.4 (CH2), 34.9 (CH3), 33.3 (CH3); IR (neat) 1745 (s), 1642 (s), 1611 (s). Methyl 4,5-bis(4-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-2-thioxoimidazolidine-4-carboxylate 48. This reaction was carried out under an inert atmosphere of dry argon. A Schleck tube was charged with imidazolinium iodide 47 (608 mg, 1.0 mmol), KOtBu (118 mg, 1.05 mmol) and S8 (256 mg, 1.0 mmol). THF (30 mL) was added and the reaction mixture was stirred at rt for 2 h. Then, water was added and the mixture was extracted with EtOAc (3×). The organic layers were dried with Na2SO4 and concentrated in vacuo. Purification using flash column chromatography (toluene visualisation on TLC with UV and with iodine) afforded 48a (229 mg, 45%) and 48b (92 mg, 18%) as white solids.

48a (most polar isomer): 1H NMR (250 MHz, CDCl3) δ (ppm) 7.12–7.03 (m, 6H), 6.82 (d, J = 8.6 Hz, 2H), 6.85–6.66 (m, 4H), 5.74 (d, J = 14.7 Hz, 1H), 5.29 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.76 (d, J = 14.7 Hz, 1H), 3.26 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 170.5 (C),

N

N

PCPMeO2C

NBoc

N

N

PCP

PCPMeO2C

PMB

+I−

N

N

PCP

PCPMeO2C

PMB

S


123

159.2 (2×C), 134.6 (C), 134.5 (C), 132.0 (C), 131.3 (C), 129.8 (4×CH), 128.6 (2×CH), 128.51 (2×CH), 128.45 (2×CH), 127.5 (C), 113.9 (2×CH), 77.8 (C), 68.1 (CH3), 55.2 (CH3), 53.3 (CH), 49.1 (CH2), 34.2 (CH3); IR (neat) 1751 (s), 1610 (m); HRMS (EI, 70 eV) calculated for C26H24Cl2N2O3S (M+) 514.0885, found 514.0902.

48b (least polar isomer): Mp 120–121 °C; 1H NMR (250 MHz, CDCl3) δ (ppm) 7.36 (d, J = 8.5 Hz, 2H), 2.50 (d, J = 8.7 Hz, 2H), 7.11–7.04 (m, 6H), 6.81 (d, J = 8.6 Hz, 2H), 5.79 (d, J = 14.6 Hz, 1H), 4.73 (s, 1H), 3.80 (s, 3H), 3.62 (d, J = 14.6 Hz, 1H), 3.28 (s, 3H), 3.08 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 183.0 (C), 168.1 (C), 159.5 (C), 136.3 (C), 135.4 (C), 135.0

(C), 133.3 (C), 130.2 (4×CH), 129.1 (2×CH), 128.1 (4×CH), 127.2 (C), 114.0 (2×CH), 77.5 (C), 70.8 (CH3), 55.3 (CH3), 52.2 (CH), 48.7 (CH2), 33.1 (CH3); IR (neat) 1737 (s), 1612 (m); HRMS (EI, 70 eV) calculated for C26H24Cl2N2O3S (M+) 514.0885, found 514.0899.

1-benzyl-3-methyl-4,5-dihydro-1H-imidazolium iodide 56. Methyl iodide (447 mg, 3.15 mmol) was added to a solution of N-benzyl-2-imidazoline 54 (480 mg, 3.0 mmol) in DCM (15 mL). The reaction mixture was stirred at rt for 18 h and concentrated in vacuo to afford 56 (0.92 g, quant.) as an orange solid. 1H NMR (250 MHz, CDCl3) δ (ppm) 9.51 (s, 1H), 7.49–7.38 (m, 5H), 4.86 (s, 2H), 4.88–3.48

(m, 4H), 3.36 (s, 3H). 1-benzyl-3-methylimidazolidin-2-one 57. To a solution of imidazolinium iodide 56 (302 mg, 1.0 mmol) in DCM (20 mL), 85% mCPBA (610 mg, 3.0 mmol) was added. The yellow solution abruptly turned red. After stirring overnight the reaction mixture was washed twice with saturated Na2CO3 (aq), dried with Na2SO4 and concentrated in vacuo to afford 57 (132 mg, 70 %) as an orange oil. 1H NMR

(250 MHz, CDCl3) δ (ppm) 7.34–7.18 (m, 5H), 4.30 (s, 2H), 3.21–3.18 (m, 2H), 3.13–3.09 (m, 2H), 2.76 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 161 (C), 137 (C), 128.7 (2×CH), 128.1 (2×CH), 127.3 (CH), 48.5 (CH2), 45.0 (CH2), 42.1 (CH2), 31.5 (CH3). Methyl 4,5-bis(4-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-2-oxoimidazolidine-4-carboxylate 58. To a cooled (0 ºC) solution of imidazolinium iodide 35 (611 mg, 1.0 mmol) in DCM (20 mL), 85% mCPBA (610 mg, 3.0 mmol) was added. The yellow solution abruptly turned red. The reaction mixture was stirred at rt for 18 h, washed twice with saturated Na2CO3 (aq), dried with Na2SO4 and concentrated in vacuo. Purification using flash column chromatography (c-hexane:EtOAc = 4:1) afforded 48a (289 mg, 58%) and 48b (120 mg, 24%) as white solids.

58a (most polar isomer): Mp 88–90 °C; 1H NMR (250 MHz, CDCl3) δ (ppm) 7.09–6.95 (m, 6H), 6.81–6.68 (m, 6H), 5.03 (s, 1H), 4.96 (d, J = 14.8 Hz, 1H), 3.79 (s, 3H), 3.79 (s, 3H), 3.52 (d, J = 14.8 Hz, 1H), 2.94 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 171.2 (C), 160.2 (C), 159.2 (C), 134.3 (C), 134.1 (C), 132.7 (C), 132.1 (C), 130.0 (4×CH), 128.6 (2×CH), 128.4

(2×CH), 128.3 (2×CH), 128.0 (C), 113.9 (2×CH), 73.8 (C), 64.3 (CH3), 55.3 (CH3), 53.0 (CH), 45.5 (CH2), 29.6 (CH3); IR (neat) 1738 (s), 1710 (s), 1611 (m); HRMS (EI, 70 eV) calculatedd for C26H24Cl2N2O4 (M+) 498.1113, found 498.1096.

58b (least polar isomer): Mp 143–145 °C; 1H NMR (200 MHz, CDCl3) δ (ppm) 7.29–6.90 (m, 10H), 6.73 (d, J = 8.7 Hz, 2H), 4.95 (d, J = 14.6 Hz, 1H), 4.39 (s, 1H), 3.72 (s, 3H), 3.40 (d, J = 14.6 Hz, 1H), 3.26 (s, 3H), 2.66 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 168.9 (C), 159.5 (C), 159.3 (C), 136.4 (C), 135.0 (C), 134.6 (C), 133.7 (C), 130.1 (2×CH), 129.6 (2×CH), 128.8

(4×CH), 128.4 (2×CH), 127.7 (C), 114.0 (2×CH), 73.7 (C), 67.2 (CH3), 55.3 (CH3), 52.0 (CH), 45.2 (CH2), 28.6 (CH3); IR (neat) 1741 (s), 1711 (s), 1611 (m); HRMS (EI, 70 eV) calculated for C26H24Cl2N2O4 (M+) 498.1113, found 498.1107.

N

N

PCP

PCPMeO2C

PMB

S

N

N+

I−

Ph

N

N

Ph

O

N

N

PCP

PCPMeO2C

PMB

O

N

N

PCP

PCPMeO2C

PMB

O

Chapter 5

124

General Procedure II for the Cleavage of PMB groups: A 0.25–0.30 M solution of imidazolidinone was refluxed for 1 h. After cooling to rt followed by evaporation of TFA, the crude product was dissolved in EtOAc, washed with saturated NaHCO3 (aq) solution and brine, dried with Na2SO4 and concentrated in vacuo. Purification was performed using flash column chromatography (c-hexane:EtOAc = 1:1, gradient).

trans-Methyl 4,5-bis(4-chlorophenyl)-3-methyl-2-oxoimidazolidine-4-carboxylate 59a. According to General Procedure II, deprotection of imidazolidinone 58a (455 mg, 0.88 mmol), followed by column chromatography, afforded 59a (304 mg, 91%) as a white solid. Mp 214–216 °C; 1H NMR (250 MHz, CDCl3) δ (ppm) 7.29–7.06 (m, 4H), 6.93 (d, J = 8.3 Hz, 2H), 6.72

(d, J = 8.4 Hz, 2H), 5.56 (s, 1H), 5.50 (br s, 1H), 3.92 (s, 3H), 2.89 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 171.4 (C), 161.1 (C), 135.8 (C), 135.2 (C), 134.4 (C), 134.0 (C), 129.0 (2×CH), 128.4 (4×CH), 128.2 (2×CH), 75.7 (C), 61.5 (CH3), 53.1 (CH), 29.1 (CH3); IR (KBr) 1734 (s), 1716 (s); HRMS (EI, 70 eV) calculated for C18H16Cl2N2O3 (M+) 378.0538, found 378.0526.

cis-Methyl 4,5-bis(4-chlorophenyl)-3-methyl-2-oxoimidazolidine-4-carboxylate 59b. According to General Procedure II, deprotection of imidazolidinone 58b (516 mg, 1.0 mmol), followed by column chromatography, afforded 59b (396 mg, 99%) as a white solid. 1H NMR (250 MHz, CDCl3) δ (ppm) 7.45 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.5

Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 5.19 (s, 1H), 4.86 (s, 1H), 3.33 (s, 3H), 2.63 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 168.6 (C), 160.8 (C), 136.1 (C), 135.8 (C), 135.1 (C), 135.0 (C), 129.1 (2×CH), 128.8 (2×CH), 128.75 (2×CH), 128.72 (2×CH), 76.0 (C), 65.1 (CH), 52.1 (CH3), 28.2 (CH3); IR (KBr) 1747 (s), 1720 (s), 1494 (m), 1435 (m); HRMS (EI, 70 eV) calculated for C18H16Cl2N2O3 (M+) 378.0538, found 378.0531. General Procedure III for the Thionation of Imidazolidinones: Reactions were performed under an inert atmosphere of dry nitrogen at a concentration of 0.020 M of imidazolidinone in dry toluene. A reaction vessel was charged with imidazolidinone (1 equiv.) and Lawesson’s reagent (1 equiv.). Toluene was added and the suspension was heated to reflux temperature. The resulting solution was refluxed for 18 h, cooled to room temperature and concentrated in vacuo. The crude product was put on a pre-packed silica column. Impurities were eluted with toluene and then the product was eluted with toluene:EtOAc = 4:1, gradient. Visualisation on TLC was performed with UV and with iodine.

trans-Methyl 4,5-bis(4-chlorophenyl)-3-methyl-2-thioxoimidazolidine-4-carboxylate 49a. According to General Procedure III, thionation of imidazolidinone 59a (1.00 g, 2.64 mmol), followed by column chromatography, afforded 49a (2.46 g, 93%) as a white solid. 1H NMR

(250 MHz, CDCl3) δ (ppm) 7.06–6.99 (m, 4H), 6.84 (d, J = 8.3 Hz, 2H), 6.60–6.55 (m, 3H), 5.63 (s, 1H), 3.86 (s, 3H), 3.10 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 184.4 (C), 170.3 (C), 134.9 (C), 134.5 (C), 133.9 (C), 130.7 (C), 128.8 (2×CH), 128.6 (2×CH), 128.4 (4×CH), 80.0 (C), 65.0 (CH), 53.5 (CH3), 33.5 (CH3); IR (KBr) 3174 (br), 1737 (s), 1596 (w), 1491 (s), 1393 (m), 1256 (s); HRMS (EI, 70 eV) calculated for C18H16Cl2N2O2S (M+) 394.0310, found 394.0303.

cis-Methyl 4,5-bis(4-chlorophenyl)-3-methyl-2-thioxoimidazolidine-4-carboxylate 49b. According to General Procedure III, thionation of imidazolidinone 59b (374 mg, 0.98 mmol), followed by column chromatography, afforded 49b (336 mg, 87%) as a white solid. 1H NMR

(250 MHz, CDCl3) δ (ppm) 7.40 (d, J = 8.9 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 8.95 (s, 1H), 5.04 (s, 1H), 3.28 (s, 3H), 2.92 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 183.9 (C), 167.4 (C), 135.7 (C), 135.32 (C), 135.28 (C), 134.8 (C), 129.3 (2×CH), 128.80 (2×CH), 128.75 (2×CH), 128.5 (2×CH), 80.1 (C), 68.8 (CH), 52.4 (CH3), 32.3 (CH3); IR (KBr) 3162 (br), 1737 (s), 1596 (w), 1491 (s), 1393 (m), 1256 (s); HRMS (EI, 70 eV) calculated for C18H16Cl2N2O2S (M+) 394.0310, found 394.0299.

N

HN

PCP

PCPMeO2C O

N

HN

PCP

PCPMeO2C O

N

HN

PCP

PCPMeO2C S

N

HN

PCP

PCPMeO2C S


125

1-Butyl-4,5-bis(4-chlorophenyl)-3-(4-methoxybenzyl)-4-(methoxycarbonyl)-4,5-dihydro-1H-imidazolium iodide 60. p-Methoxybenzyl bromide (1.46 g, 7.28 mmol) was added to a solution of imidazoline 37 (2.95 g, 7.28 mmol) and NaI (1.09 g, 7.28 mmol) in acetone (90 mL). The reaction mixture was stirred at rt for 18 h, filtered and concentrated in vacuo to afford 60 (4.75 g, quant.) as a 74:26 mixture of diastereomers as a white solid. 1H NMR (400

MHz, CDCl3) δ (ppm) 9.40 (s, 1H), 9.27 (s, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.47–7.42 (m, 2H + 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.16–7.07 (m, 6H + 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.91–6.86 (m, 4H), 6.16 (s, 1H), 5.59 (s, 1H), 5.21 (d, J = 14.5 Hz, 1H), 4.66 (d, J = 14.5 Hz, 1H), 4.52 (d, J = 13.6 Hz, 1H), 4.35 (d, J = 13.7 Hz, 1H), 3.89 (s, 3H), 3.89–3.82 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.79–2.65 (m, 1H), 3.38–3.35 (m, 1H), 3.36 (s, 3H), 3.26–3.19 (m, 1H), 1.71–1.57 (m, 2H + 2H), 1.32–1.21 (m, 2H + 2H), 0.90–0.84 (m, 3H + 3H); 13C NMR (101 MHz, CDCl3) δ (ppm) 169.0 (C), 166.0 (C), 160.1 (C), 158.6 (2×CH), 156.2 (C), 136.9 (C), 136.8 (C), 135.9 (C), 135.8 (C), 133.2 (C), 132.2 (C), 131.7 (2×CH), 130.3 (2×CH), 130.1 (2×CH), 129.93 (C), 129.89 (2×CH), 129.7 (2×CH), 129.5 (2×CH), 129.4 (2×CH), 129.20 (2×CH), 129.17 (2×CH), 129.1 (2×CH), 128.6 (C), 125.7 (C), 124.0 (C), 114.8 (2×CH), 114.6 (2×CH), 80.7 (C), 80.6 (C), 76.9 (CH), 71.4 (CH), 55.4 (CH3), 55.3 (CH3), 54.4 (CH3), 53.0 (CH3), 50.6 (CH2), 50.3 (CH2), 47.6 (CH2), 47.3 (CH2), 29.3 (CH2), 29.0 (CH2), 19.6 (CH2), 19.5 (CH2), 13.5 (CH3), 13.4 (CH3); IR (KBr) 1641 (s), 1513 (m), 1250 (s).

Methyl 1-butyl-4,5-bis(4-chlorophenyl)-3-(4-methoxybenzyl)-2-oxoimidazolidine-4-carboxylate 61. To a cooled (0 ºC) solution of imidazolinium iodide 60 (265 mg, 0.41 mmol) in DCM (8 mL), 85% mCPBA (247 mg, 1.22 mmol) was added. The yellow solution abruptly turned dark orange. The reaction mixture was stirred at rt for 18 h, while a colour change from dark orange to light pink to dark red was observed. Then, the reaction mixture was washed

twice with saturated Na2CO3 (aq), dried with Na2SO4 and concentrated in vacuo. Purification using flash column chromatography (pentane:EtOAc = 7:1, visualisation on TLC with CerMOP) afforded 61 as a 76:24 mixture of diastereomers as a white solid. 1H NMR (250 MHz, CDCl3) δ (ppm) 7.42–7.27 (m, 8H), 7.17–7.06 (m, 8H), 6.88–6.62 (m, 2H + 4H), 6.60 (d, J = 8.7 Hz, 2H), 5.58 (s, 1H), 4.96 (d, J = 15.9 Hz, 1H), 4.81 (s, 1H), 4.35 (d, J = 15.1 Hz, 1H), 4.18–4.11 (m, 1H + 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.73–3.60 (m, 1H + 1H), 3.38 (s, 3H), 3.23 (s, 3H), 2.75–2.64 (m, 1H + 1H), 1.54–1.22 (m, 4H + 4H), 0.99–0.85 (m, 3H + 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 170.5 (C), 168.9 (C), 160.7 (C), 160.3 (C), 158.5 (2×C), 137.3 (C), 134.9 (C), 134.6 (C), 134.3 (C), 134.1 (C), 133.8 (C), 132.7 (C), 132.6 (C), 130.9 (C), 130.3 (C), 129.7 (2×CH), 128.9 (2×CH), 128.7 (4×CH + 4× CH), 128.2 (2×CH), 128.2 (2×CH), 127.9 (2×CH + 2×CH), 113.7 (2×CH), 113.4 (2×CH), 74.0 (C), 73.8 (C), 69.1 (CH), 64.7 (CH), 55.24 (CH3), 55.20 55.2 (CH3), 52.7 55.2 (CH3), 51.8 55.2 (CH3), 46.8 (CH2), 46.0 (CH2), 42.0 (CH2), 41.8 (CH2), 29.0 (CH2), 28.8 (CH2), 20.0 (CH2), 19.9 (CH2), 13.74 (CH3), 13.67 (CH3); IR (KBr) 1707 (s), 1513 (s), 1244 (s); HRMS (EI, 70 eV) calculated for C29H30Cl2N2O4 (M+) 540.1583, found 540.1587.

Methyl 1-butyl-4,5-bis(4-chlorophenyl)-2-oxoimidazolidine-4-carboxylate 62. According to General Procedure II, deprotection of imidazolidinone 61 (2.15 g, 3.97 mmol), followed by column chromatography, afforded 62 (1.57 g, 94%) as a 75:25 mixture of diastereomers as a white solid. 1H NMR (250 MHz, CDCl3) δ (ppm) 7.66 (d, J = 8.8 Hz, 2H), 7.43–7.38 (m, 4H),

7.29 (d, J = 8.5 Hz, 2H), 7.13–7.09 (m, 6H), 6.91 (d, J = 8.5 Hz, 2H), 5.90 (s, 1H), 5.50 (s, 1H), 5.47 (s, 1H), 4.77 (s, 1H), 3.82 (s, 3H), 3.65–3.51 (m, 1H + 1H), 3.35 (s, 3H), 2.60–2.48 (m, 1H + 1H), 1.47–1.35 (m, 2H), 1.33–1.13 (m, 2H + 2H), 1.10–1.07 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H), 0.77 (t, J = 7.1 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 172.5 (C), 169.3 (C), 160.0 (C), 159.4 (C), 139.3 (C), 135.0 (C), 134.7 (C), 134.5 (C), 134.3 (C), 134.2 (C), 133.5 (C), 133.1 (C), 128.9 (2×CH), 128.9 (2×CH), 128.49 (2×CH), 128.46 (2×CH), 127.3 (4×CH), 127.2 (4×CH), 70.3 (CH), 69.4 (C), 68.9 (C), 65.7 (CH), 53.5 (CH3), 52.6 (CH3), 41.0 (CH2), 40.6 (CH2), 29.4 (CH2), 29.3 (CH2), 19.7 (CH2), 19.6 (CH2), 13.6 (CH3), 13.5 (CH3); IR (KBr) 3233 (br), 2956 (m), 1701 (s), 1492 (s), 1231 (s), 1092 (s); HRMS (EI, 70 eV) calculated for C21H22Cl2N2O3 (M+) 420.1007, found 420.0989.

N

N

PCP

PCPMeO2C

PMB

+I−

N

N

PCP

PCPMeO2C

PMB

O

NH

N

PCP

PCPMeO2C O

Chapter 5

126

Methyl 1-butyl-4,5-bis(4-chlorophenyl)-2-thioxoimidazolidine-4-carboxylate 63. According to General Procedure III, thionation of imidazolidinone 62 (250 mg, 0.59 mmol), followed by column chromatography, afforded 63 as a 76:24 mixture of diastereomers as a white solid (245 mg, 94%). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.63 (d, J = 8.7 Hz, 2H),

7.43 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 7.28–7.20 (m, 2H), 7.15–7.10 (m, 6H), 7.04 (d, J = 8.7 Hz, 2H), 6.86 (s, 1H), 6.84 (s, 1H), 5.70 (s, 1H), 4.92 (s, 1H), 4.22–4.14 (m, 1H), 4.09–4.05 (m, 1H), 3.83 (s, 3H), 3.38 (s, 3H), 2.79–2.72 (m, 1H), 2.67–2.63 (m, 1H), 1.57–1.49 (m, 2H), 1.35–1.26 (m, 2H + 2H), 1.09–1.03 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ (ppm) 182.9 (C), 181.8 (C), 171.4 (C), 167.9 (C), 136.2 (C), 135.5 (C), 135.2 (C), 134.7 (2×C), 133.4 (C), 132.6 (C), 131.9 (C), 129.2 (2×CH), 128.7 (4×CH), 128.7 (4×CH), 127.2 (4×CH), 126.8 (2×CH), 74.4 (CH), 72.4 (C), 72.2 (C), 69.7 (CH), 53.8 (CH3), 52.8 (CH3), 45.0 (CH2), 44.3 (CH2), 29.1 (CH2), 28.9 (CH2), 19.7 (CH2), 19.4 (CH2), 13.7 (CH3), 13.5 (CH3); IR (KBr) 3162 (br), 2952 (s), 1729 (s), 1593 (m), 1491 (s), 1231 (s); HRMS (EI, 70 eV) calculated for C21H22Cl2N2O2S (M+) 436.0779, found 436.0777. General Procedure IV for the microwave assisted Liebeskind-Srogl reactions: A dry microwave vessel was charged with 0.25 mmol imidazolidine-2-thione, 0.38 mmol aryl boronic acid, Cu(I) thiophene-2-carboxylate (144.7 mg, 0.75 mmol) and Pd(PPh3)4 (8.9 mg, 7.5 μmol). The vessel was flushed with Ar and sealed. Dry DMF was added through the septum and the reaction mixture was irradiated in the microwave at 130 ºC for the 1 h, unless stated otherwise. After cooling, DMF was removed in vacuo at 50 ºC. The crude mixture was diluted with saturated NaHCO3 (aq) and extracted with DCM. The organic layer was washed twice with saturated NaHCO3 (aq), dried with Na2SO4 and concentrated in vacuo. Purification was performed with flash column chromatography (c-hexane:EtOAc:Et3N = 5:1:0.01, gradient).

Methyl 1-butyl-4,5-bis(4-chlorophenyl)-2-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate 64. According to General Procedure IV, arylation of imidazolidin-2-thione 63 (109 mg, 0.25 mmol) with phenyl boronic acid (46 mg, 0.38 mmol) followed by column chromatography afforded 64 (78 mg, 65%) as a 75:25 mixture of diastereomers as a yellow

solid. 1H NMR (250 MHz, CDCl3) δ (ppm) 7.82 (d, J = 8.7 Hz, 2H), 7.68–7.64 (m, 2H + 2H), 7.50–7.47 (m, 3H + 3H), 7.40–7.33 (m, 2H), 7.09–6.92 (m, 8H + 4H), 5.73 (s, 1H), 4.95 (s, 1H), 3.78 (s, 3H), 3.31–3.21 (m, 1H + 1H), 3.25 (s, 3H), 2.85–2.79 (m, 1H + 1H), 1.37–1.06 (m, 4H + 4H), 0.71 (t, J = 7.2 Hz, 3H), 0.59 (t, J = 7.2 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 174.5 (C), 171.4 (C), 167.7 (C), 167.1 (C), 143.1 (2×C), 135.9 (C), 134.5 (C), 133.3 (C), 132.6 (C), 132.4 (C), 131.9 (C), 130.0 (2×C), 131.0 (CH), 130.8 (C), 130.2 (2×CH), 129.6 (2×CH), 129.1 (2×CH), 128.99 (2×CH), 128.97 (2×CH + 2×CH), 128.9 (2×CH), 128.8 (2×CH + 2×CH), 128.7 (2×CH), 128.6 (2×CH), 128.2 (2×CH), 82.8 (C), 82.6 (C), 75.4 (CH), 70.3 (CH), 53.5 (CH3), 52.6 (CH3), 45.9 (CH2), 45.8 (CH2), 30.6 (CH2), 30.1 (CH2), 19.8 (CH2), 19.4 (CH2), 13.9 (CH3), 13.7 (CH3); IR (KBr) 2928 (s), 1726 (s), 1490 (s), 1241 (s); HRMS (EI, 70 eV) calculated for C25H23Cl2N2 (M+−CO2Me) 421.1238, found 421.1223, molecular ion could not be detected.

Methyl 1-butyl-4,5-bis(4-chlorophenyl)-2-(4-methoxyphenyl)-4,5-dihydro-1H-imidazole-4-carboxylate 65. According to General Procedure IV, arylation of imidazolidin-2-thione 63 (109 mg, 0.25 mmol) with p-methoxyphenyl boronic acid (58 mg, 0.38 mmol) followed by column chromatography afforded 65 (71 mg, 55%) as a 75:25 mixture of diastereomers as a

yellow solid, together with starting material 63 (14 mg, 13%). 1H NMR (250 MHz, CDCl3) δ (ppm) 7.81 (d, J = 8.5 Hz, 2H), 7.68–7.60 (m, 2H + 2H), 7.39–7.36 (m, 2H), 7.08–6.90 (m, 10H + 6H), 5.70 (s, 1H), 4.90 (s, 1H), 3.87 (s, 3H + 3H), 3.77 (s, 3H), 3.33–3.23 (m, 1H + 1H), 3.23 (s, 3H), 2.88–2.80 (m, 1H + 1H), 1.33–1.01 (m, 4H + 4H), 0.85 (t, J = 6.0 Hz, 3H), 0.72 (t, J = 7.2 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 174.6 (C), 171.6 (C), 167.5 (C), 166.9 (C), 161.8 (C), 161.7 (C), 143.3 (2×C), 137.5 (C), 136.2 (C), 134.6 (C), 134.0 (C), 133.7 (C), 133.3 (C), 130.7 (2×CH), 130.5 (2×CH), 130.2 (2×CH + 2×CH), 129.6 (2×CH), 129.1 (2×CH), 128.8 (2×CH), 128.7 (2×CH), 128.6 (2×CH), 128.1 (2×CH), 123.1 (C), 123.0 (C), 114.6 (2×CH), 114.3 (2×CH), 82.8 (C), 82.5

NH

N

PCP

PCPMeO2C S

N

N

PCP

PCPMeO2C Ph

N

N

PCP

PCPMeO2C PMP


127

(C), 75.5 (CH), 70.3 (CH), 55.8 (CH3 + CH3), 53.5 (CH3), 52.5 (CH3), 46.3 (CH2), 46.2 (CH2), 30.2 (CH2), 30.1 (CH2), 20.1 (CH2), 19.8 (CH2), 14.0 (CH3), 13.8 (CH3); IR (KBr) 2924 (s), 1734 (s), 1611 (s), 1490 (s), 1251 (s); HRMS (EI, 70 eV) calculated for C26H25Cl2N2 (M+−CO2Me) 451.1344, found 451.1336, molecular ion could not be detected.

trans-Methyl 4,5-bis(4-chlorophenyl)-1-methyl-2-phenyl-4,5-dihydro-1H-imidazole-5-carboxylate 66. According to General Procedure IV, arylation of imidazolidin-2-thione 49a (100 mg, 0.25 mmol) with phenyl boronic acid (46 mg, 0.38 mmol) followed by column chromatography afforded 66 (56 mg, 51%) as a yellow solid together with starting material 49a

(2 mg, 2%). 1H NMR (250 MHz, CDCl3) δ (ppm) 7.79–7.68 (m, 2H), 7.57–7.45 (m, 3H), 7.06 (d, J = 8.6 Hz, 2H), 7.03 (s, 4H), 6.79 (d, J = 8.5 Hz, 2H), 5.96 (s, 1H), 3.97 (s, 3H), 2.87 (s, 3H); 13C NMR (63 MHz, CDCl3) δ (ppm) 173.2 (C), 165.5 (C), 137.4 (C), 133.6 (C), 133.0 (C), 132.5 (C), 130.8 (C), 130.8 (CH), 129.5 (2×CH), 128.7 (2×CH), 128.5 (2×CH), 128.4 (2×CH), 128.1 (2×CH), 127.6 (2×CH), 81.1 (C), 76.0 (CH), 52.9 (CH3), 33.0 (CH3); IR (KBr) 1726 (s), 1589 (m), 1487 (m), 1379 (m), 1231 (m); HRMS (EI, 70 eV) calculated for C24H20Cl2N2O2 (M+) 438.0902, found 438.0883.

trans-Methyl 4,5-bis(4-chlorophenyl)-2-(4-methoxyphenyl)-1-methyl-4,5-dihydro-1H-imidazole-5-carboxylate 67. According to General Procedure IV, arylation of imidazolidin-2-thione 49a (100 mg, 0.25 mmol) with p-methoxyphenyl boronic acid (58 mg, 0.38 mmol)

followed by column chromatography afforded 67 (48 mg, 41%) as a yellow solid, together with starting material 49a (5 mg, 5%). 1H NMR (250 MHz, CDCl3) δ (ppm) 7.69 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.01 (br s, 6H), 6.77 (d, J = 8.5 Hz, 2H), 5.92 (br s, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 2.89 (s, 3H); IR (KBr); HRMS (EI, 70 eV) calculated for C25H22Cl2N2O3 (M+) 468.1007, found 468.1002.


[1] Bousquet, P.; Feldman, J.; Schwartz, J. J. Pharmacol. Exp. Ther. 1984, 230, 232–236. [2] For a recent review about imidazoline binding sites and their ligands, see: Dardonville, C.; Rozas, I. Med.

Res. Rev. 2004, 24, 639–661. [3] a) Gust, R.; Keilitz, R.; Schmidt, K.; von Rauch, M. J. Med. Chem. 2002, 45, 3356–3365. b) von Rauch, M.;

Schlenk, M.; Gust, R. J. Med. Chem. 2004, 47, 915–927. c) von Rauch, M.; Busch, S.; Gust, R. J. Med. Chem. 2005, 48, 466–474.

[4] Schäfer, U.; Burgdorf, C.; Engelhardt, A.; Kurz, T.; Richardt, G. J. Pharmacol. Exp. Ther. 2002, 303, 1163–1170.

[5] Milhaud, D.; Fagni, L.; Bockaert, J.; Lafon-Cazal, M. Neuropharmacology 2000, 39, 2244–2254. [6] a) Boswell, G.; Li, H.-Y.; Delucca, I.; Billheimer, J. T.; Drummond, S.; Gillies, P. J.; Robinson, C. Bioorg.

Med. Chem. Lett. 1996, 6, 885–888. b) Li H.; Drummond, S.; Delucca, I.; Boswell, G. Tetrahedron 1996, 52, 11153–11162. c) Li, H.-Y.; Delucca, I.; Boswell, G. A.; Billheimer, J. T.; Drummond, S.; Gillies, P. J.; Robinson, C. Bioorg. Med. Chem. 1997, 5, 1345–1361.

[7] Ferretti, G.; Dukat, M.; Giannella, M.; Piergentili, A.; Pigini, M.; Quaglia, W.; Damaj, M. I.; Martin, B. R.; Glennon, R. A. J. Med. Chem. 2002, 45, 4724–4731.

[8] a) Prisinzano, T.; Law, H.; Dukat, M.; Slassi, A.; MaClean, N.; Demchyshyn, L.; Glennon, R. A. Bioorg. Med. Chem. 2001, 9, 613–619. b) Prisinzano, T.; Dukat, M.; Law, H.; Slassi, A.; MaClean, N.; DeLannoy, I.; Glennon, R. A. Bioorg. Med. Chem. Lett. 2004, 14, 4697–4699. c) Law, H. Dukat, M.; Teitler, M.; Lee, D. K.; Mazzocco, L.; Kamboj, R.; Rampersad, V.; Prisinzano, T.; Glennon, R. A. J. Med. Chem. 1998, 41, 2243–2251.

[9] a) Doyle, M. E.; Egan, J. M. Pharmacol. Rev. 2003, 55, 105–131. b) Rondu, F.; le Bihan, G.; Wang, X.; Lamouri, A.; Touboul, E.; Dive, G.; Bellahsene, T.; Pfeiffer, B.; Renard, P.; Guardiola-Lemaitre, B.; Manechez, D.; Penicaud, L.; Ktorza, A.; Godfroid, J.-J. J. Med. Chem. 1997, 40, 3793−3803.

[10] Ueno, M.; Imaizumi, K.; Sugita, T.; Takata, I.; Takeshita, M. Int. J. Immunopharmac. 1995, 17, 597–603.

N

N

PCP

PCPMeO2C Ph

N

N

PCP

PCPMeO2C PMP

Chapter 5

128

[11] a) Bousquet, P.; Feldman, J. Drugs, 1999, 58, 799–812. b) Touzeau, F.; Arrault, A.; Guillaumet, G.; Scalbert, E.; Pfeiffer, B.; Rettori, M.-C.; Renard, P.; Mérour, J.-Y. J. Med. Chem. 2003, 46, 1962–1979.

[12] MDM2 is an abbreviation for murine double minute 2. The human version of MDM2 is actually called HDM2 (human double minute 2). Although in vitro research on the p53-MDM2 interaction is often, but not always, done with human tissue (so with HDM2), the in vivo experiments mentioned in this thesis were performed with mice. Further, some structural studies were done with specially engineered hybrids of HDM2 and the frog (Xenopus) version of the protein (reference 23). In literature, the formally incorrect terms MDM2 and human MDM2 are often used when HDM2 or hybrid proteins are meant. For the sake of clarity, also in this thesis only the name MDM2 will be used.

[13] Vassilev, L. T.; Vu, B. T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.; Liu, E. A. Science 2004, 303, 844–848.

[14] a) Sharma, V.; Lansdell, T. A.; Peddibhotla, S.; Tepe, J. J.; Chem. Biol. 2004, 11, 1689–1699. b) Sharma, V.; Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2006, ASAP.

[15] Vogelstein, B.; Lane, D.; Levine, A. J. Nature 2000, 408, 307–310 and references cited therein. [16] Momand, J.; Wu, H. H.; Dasgupta, G. Gene 2000, 242, 15–29 (review on the regulation of p53 by MDM2). [17] Chene, P. Nat. Rev. Cancer 2003, 3, 102–109 (review). [18] a) Chen, L. H.; Agrawal, S.; Zhou, W. Q.; Zhang, R. W.; Chen, J. D. Proc, Natl. Acad. Sci. U.S.A. 1998, 95,

195–200. b) Wasylyk, C.; Salvi, R.; Argentini, M.; Dureuil, C.; Delumeau, I.; Abecassis, J.; Debussche, L.; Wasylyk, B. Oncogene 1999, 18, 1921–1934. c) Tortora, G.; Caputo, R.; Damiano, V.; Bianco, R.; Chen, J. D.; Agrawal, S.; Bianco, A. R.; Ciardiello, F. Int. J. Cancer 2000, 88, 804–809.

[19] Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Tominta, Y.; Parrish, D. A.; Deschamps, J. R.; Wang, S. J. Am. Chem. Soc. 2005, 127, 10130–10131.

[20] Garcia-Echeverria, C.; Chene, P.; Blommers, M. J. J.; Furet, P. J. Med. Chem. 2000, 43, 3205–3208. [21] Carvajal, D.; Tovar, C.; Yang, H.; Vu, B. T.; Heimbrook, D. C.; Vassilev, L. T. Cancer Res. 2005, 65, 1918–

1924. [22] Picksley, S. M.; Vojtesek, B.; Sparks, A.; Lane, D. P. Oncology 1994, 9, 2523–2529. [23] Fry, D. C.; Emerson, S. D.; Palme, S.; Vu, B. T.; Liu, C.-M.; Podlaski, F. J. Biomol. NMR 2004, 30 163–173. [24] Zhong, H.; Carlson, H. A. Proteins: Struct. Funct. Genet. 2005, 58, 222–234. [25] Sharma, V.; Tepe, J. J. Org. Lett. 2005, 7, 5091–5094. [26] a) Bon, R. S.; Hong, C.; Bouma, M. J.; Schmitz, R. F.; de Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Orru,

R. V. A. Org. Lett. 2003, 5, 3759–3762. b) Bon, R. S.; van Vliet, B.; Sprenkels, N. E.; Scmitz, R. F.; de Kanter, F. J. J.; Stevens, C. V.; Swart, M.; Bickelhaupt, F. M.; Groen, M. B.; Orru, R. V. A. J. Org. Chem. 2005, 70, 3542–3553.

[27] The trans isomers show a characteristic upfield shift of H–5 in 1H NMR, resulting from the shielding effect of the p-chlorophenyl group at C–4. See also reference 26a.

[28] a) Lewis, J. C.; Wiedeman, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35–38. b) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 2685–2686.

[29] Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274–5275. [30] a) Sprenkels, N. E. Follow-up Chemistry on 2-Imidazolines, Master thesis 2006, Vrije Universiteit

Amsterdam. b) Osman, D. A. Studies towards Synthesis and Cyclisation of Imidazoles and 2-Imidazolines, Bachelor thesis 2006, Vrije Universiteit Amsterdam/Hogeschool Leiden.

[31] a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260–11261. b) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979–982. c) Kusturin, C. L.; Liebeskind, L. S.; Neumann, W. N. Org. Lett. 2002, 4, 983–985.

[32] Kusturin, C. L.; Liebeskind, Rahman, H.; Sample, K.; Schweitzer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5, 4349–4352.

[33] Lengar, A.; Kappe, C. O. Org. Lett. 2004, 6, 771–774. [34] a) Pedersen, B. S.; Scheibye, S.; Nisson, N. H.; Lawesson, S.-O. Bull. Soc. Chim. Belg. 1978, 87, 223–232. b)

For a review on the applications of this reagent, see: Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061–5087.


129

[35] a) Bartmann, W.; Beck, G.; Lau, H. H.; Wess, G. Tetrahedron Lett. 1984, 25, 733–736. b) Karkhanis, D. W.; Field, L. Phosphorus Sulphur 1985, 22, 49–57. c) Cow, C. N.; Harrison, P. H. M. J. Org. Chem. 1997, 62, 8834–8840.

[36] Kaiya, T.; Aoyama, S.; Kohda, K. Bioorg. Med. Chem. Lett. 1998, 8, 625–630. [37] Oumouch, S.; Bourotte, M.; Schmitt, M; Bourguignon, J.-J. Synthesis 2005, 25–27.

Chapter 6

Multicomponent Synthesis of 3,4-Dihydro-2-pyridones

Robin S. Bon,a Monica Paravidino,a Rachel Scheffelaar,a Anass Znabet,a Danielle J. Vugts,a Rob F. Schmitz,a Frans J.J. de Kanter,a Martin Lutz,b Anthony L. Spek,b Marinus B. Groen,a Romano V.A.

Orrua




Abstract: A highly diastereoselective multicomponent reaction between diethyl methylphosphonate, nitriles, aldehydes and isocyanoacetates gives access to a diverse range of 3-isocyano-3,4-dihydro-2-pyridones. The MCR is flexible with respect to the nitrile, aldehyde and isocyanoacetate substituents, although aliphatic and highly electron withdrawing aldehyde substituents are not suitable. Preliminary experiments show that also isocyanoacetates lacking an additional EWG can be applied. The free amido nitrogen and the isocyano group make the products excellent candidates for further derivatisation to diverse libraries of Freidinger-type β-turn mimics. Preliminary mechanistic studies have been performed using semiempirical and DFT calculations.

Chapter 6

132

6.1 Introduction

If one compares a living system to an ant colony, proteins act as both workers and soldiers, all appearing to have an individual agenda, yet being part of a complex organisation. They are responsible for processes like catalysis, transport and storage of molecules, mechanical support, immune protection, movement, transmission of nerve impulses, growth and differentiation. Therefore, proteins are involved in most physiological and pathological processes. However, the possibilities for developing native proteins as drugs are limited due to their poor bioavailability, antigenicity and unfavourable pharmacokinetics and because they are susceptible to proteolysis. In many biological regulatory mechanisms, molecular recognition processes between (i) proteins and nucleic acids; (ii) proteins and proteins; and (iii) proteins and small molecules are indispensable. Proteins tend to exert their biological activity through small regions of their folded surfaces. An important class of secondary structures involved in recognition processes are reverse turn conformations.1 Reverse turns connect protein structural elements such as α-helices and β-sheets and they change the overall direction of the polypeptide chain. They are polar and located predominantly on the surface of proteins. Hence, reverse turns are often very important for receptor binding and antibody recognition and they play an active role in protein folding.

Figure 1. Schematic diagram of a β-turn

A well studied subset of the reverse turn comprises the β-turns,1 whose importance was first recognised in 1968 when Venkatachalam classified β-turns into conformational types.2 A β-turn is defined as any tetrapeptide sequence in which the Cαi–Cαi+3 spatial distance is ≤ 7 Å and which occurs in a non-helical region (Figure 1).3 Consequently, the backbone conformation is highly variable (for example, the Cαi–Cαi+3 distance varies from 4–7 Å). Classifications of β-turns are based on the φ and ψ peptide backbone torsion angles.2,4 In some cases, β-turns are stabilised by an intramolecular hydrogen bond between the carbonyl oxygen of residue i and the amide of residue i+3, forming a 10-membered ring. In the β-turn, both the type of functional groups and the topology of the peptide are important for molecular recognition. In the last two decades, the strategic design and synthesis of organic molecules that topographically mimic β-turns has evolved markedly.5 Especially the application of conformational constraints in peptide secondary structure mimics6 has proven its value, rendering bioactive agents that are more potent, more specific and more

Multicomponent Synthesis of Dihydropyridones

133

stable against proteolysis and sometimes even suitable for oral administration.1a,7 This way, the problems connected with the therapeutic use of peptides are circumvented and information about the receptor-bound conformation may be provided. In addition, protein structure and function can be studied using β-turn mimics.

Chart 1

Because of their wide variety in structure, it should be clear that there can impossibly be a single molecular scaffold that accurately mimics the diversity of β-turns. One approach to construct β-turn mimics involves the synthesis of α-amino substituted γ-, δ- and ε-lactams. These cyclic motives provide a rigid peptide containing framework that can bear an assortment of additional functional groups. Several conformationally restricted δ-lactams have been incorporated into longer peptide sequences. Kemp and his co-workers were able to model the β-turn topology using δ-lactams of type 1, in which the Cαi and Cαi+1 are tethered (Chart 1).8 Additional conformational constraint is induced by intramolecular hydrogen bonding. Alternatively, Freidinger developed α-amino lactams of type 2 containing a tether between the Cαi and Ni+1 atoms as type βII-turn mimics.9 Several sets of Freidinger-type lactams have been prepared and evaluated as, for example, inhibitors of angiotensin converting enzyme (ACE)10 and modulators of dopaminergic receptors in the central nervous system.11

6.2 Multicomponent Synthesis of 3,4-Dihydro-2-pyridones

In our group, a novel multicomponent synthesis of functionalised dihydropyrimidine-2-ones 8 was developed recently.12 The MCR involves the in situ generation of 1-azadienes 6 via a Horner-Wadsworth-Emmons reaction followed by a formal aza-Diels-Alder reaction with an electron poor isocyanate 7 (Scheme 1). Allowing the intermediate azadiene to react with other dienophiles gives access to different heterocyclic scaffolds like triazinanediones 9,12 2-aminothiazines 11,12b and dihydropyrimidine-2-thiones 12.13 In our continuing efforts to explore the potential of isocyanides containing acidic α-protons,14 we examined the reaction between diethyl methylphosphonate 3, benzonitrile 13, p-methoxybenzaldehyde 14 and methyl 2-isocyano-2-phenylacetate 16 (Scheme 2). In contrast to related multicomponent reactions,14 the isocyano group of 16 is not incorporated in the ring, but stays intact. The resulting 3-isocyano-3,4-dihydro-2-pyridone 17, which was isolated as a

Chapter 6

134

single diastereomer, was immediately recognised for its potential in the construction of Freidinger-type β-turn mimics.

Scheme 1

Dihydropyridone 17 contains a rigid framework with a double bond suitable for further funtionalisation, e.g., reduction,15 epoxidation,16 or [2+2]-photocycloadditions.17 Moreover, the α-isocyano group is an excellent synthetic handle for additional multicomponent chemistry leading to peptidic structures. Finally, also the free amido nitrogen is a versatile anchor for derivatisation.

Scheme 2a

a Reagents and conditions: (a) n-BuLi, THF, −78 °C to rt, 5 h. (b) THF, rt., 18 h. PMP = p-methoxyphenyl.

Because 3,4-dihydro-2-pyridones are conformationally similar to dihydropyridines, they may have great potential as calcium channel modulators.18 Furthermore, 3,4-dihydro-2-pyridones have been used extensively as intermediates for the synthesis of complex natural products.19 Numerous routes to 3,4-dihydro-2-pyridones are known, many of which involve variants of the aza-annulation of enamines and carboxylic acid derivatives or nitriles.6d,18b,19,20 Also some reactions between (N-substituted) 1-azadienes and oxazolones,21 ketenes22 or α-metallated acetate derivatives23 have been reported. However, the possibilities for differentiation displayed by 17 are unprecedented and to the best of our knowledge, no multicomponent reactions have been reported that lead to heterocycles containing isocyano substituents. Therefore, we decided to investigate the scope of this novel multicomponent reaction.


135

The one-pot combination of a diverse range of aldehydes with phosphonate 3, benzonitrile 13 and isocyanoacetate 16 is depicted in Table 1. The choice of the aldehyde proved to be of crucial importance. Aromatic and heteroaromatic aldehydes perform well and give the expected dihydropyridones in reasonable to excellent yield (entries 1, 2 and 4 and Scheme 2). Strongly electron deficient p-nitrobenzaldehyde 22 represents an evident exception and leads to a complex mixture of unidentified products (entry 3).

Table 1. One-pot reaction between 3, 13, 16 and various aldehydes entry aldehyde product yielda entry aldehyde product yielda

1

O18

Cl

NH

O

PCP

Ph

PhNC

19

72%b 5 O

26

NH

OPh

PhNC

27

0%d

2

O20

NH

O

Ph

Ph

PhNC

21

98%b 6 O

28

NH

OPh

PhNC

29

0%c

3

O22

NO2

NH

O

PNP

Ph

PhNC

23

0%c 7

O

30

NH

OPh

PhNC

31

64%b

4

O

O

24

NH

OPh

PhNC

25

O

36%b 8

O

32

NH

OPh

PhNC

33

77%b,e

a Isolated yields are reported. b Only the 3,4-cis-diastereomer could be detected in the 1H NMR of the crude product. c A mixture of unidentified products was isolated instead. d An unidentified mixture of products resulting from aldol condensations was isolated instead. e A 1:1 mixture of epimers was isolated. PCP = p-chlorophenyl, PNP = p-nitrophenyl.

Application of aliphatic aldehydes was less successful. When isobutyraldehyde 26 was

tested as aldehyde input, a mixture of products resulting from aldol condensations was isolated (entry 5). Blocking the α-position of the aldehyde did not solve this problem, because also the reaction with pivaldehyde 28 did not give any dihydropyridone (entry 6). Probably, the steric bulk of the t-butyl group prevents attack to the in situ formed azadiene. However, the suitability of α,β-unsaturated aldehydes was demonstrated using

Chapter 6

136

1-cyclohexene-1-carboxaldehyde 30 and (1R)-(−)-myrtenal 32 (entries 7 and 8), leading to high yields.

Figure 2. Displacement ellipsoid plot of the centrosymmetric, hydrogen bonded dimer of 20, drawn at the 50% probability level. The intermolecular H…O distance is 2.009(19) Ǻ.

In all cases, only the 3,4-cis-isomers were formed. Use of the optically pure myrtenal 32 did not show any chiral induction, so 33 was isolated as a 1:1 mixture of epimers. The X-ray crystal structure of 21, which show a centrosymmetric, hydrogen bridged dimer with intermolecular H…O distances of 2.009(19) Ǻ, unambiguously confirms the cis relationship between the isocyano group at C–3 and the phenyl group at C–4 (Figure 2). In addition, the stereochemical relationships in all reported dihydropyridones were confirmed using NOESY measurements, which displayed clear nuclear Overhauser effects between the ortho-protons of the phenyl group at C–3 and the proton at C–4. Both the crystal structure of 21 (Figure 2) and Spartan optimised structures of the dihydropyridones (B3LYP 6–31G*) show the close proximity of these protons in the 3,4-cis diastereomers (1.7–2.5 Ǻ) compared to the 3,4-trans diastereomers (3.1–4.3 Ǻ) (Table 3).

Also the applicability of different nitriles in the multicomponent reaction was

investigated. R1 substituents with a variety of electronic features appear compatible with the reaction conditions. Besides aromatic nitriles (Table 1), both aliphatic and heteroaromatic nitriles give good results (Table 2, entries 1 and 2). However, primary aliphatic nitriles


137

should be avoided as they are known to be less efficient in the generation of the azadiene intermediate 6.12,24 Finally, the isocyanoacetate component was varied. Methyl 2-isocyano-2-(4-chlorophenyl)acetate 38 also proved an appropriate isocyanoacetate that gives the expected highly diastereoselective Michael addition/lactamisation cascade in good yields (entries 3 and 4).

Table 2. Variation of the nitrile and isocyanoacetate componentsa entry nitrile aldehyde isocyanoacetate product yield (dr)b

1 CN

34 O14

OMe

NH

O

PMPPh

NC

35

57%c

2 CN

O

36 O14

OMe

NH

O

PMPPh

NC

37O

76%c

3 CN

13 O14

OMe

NH

O

PMP

Ph

PCPNC

39

60%c

4 CN

13 O

18

NH

O

Ph

Ph

PCPNC

40

60%c

5 CN

13 O14

OMe

MeO2C NC

41

NH

O

PMP

Ph

42

NC

32% (63:37)d,e

a In all reactions, diethyl methylphosphonate 3 was used as the phosphonate component. b Isolated yields are reported. c Only the 3,4-cis-diastereomer could be detected in the 1H NMR of the crude product. d For this reaction, the azadiene from 3, 13 and 14 was added slowly to a solution containing the isocyanoacetate 41. Addition of 41 to a solution of azadiene resulted in isolation of 42 (19%, 67:33) together with byproduct 44 (18%). e Relative stereochemistry was determined from the 3J between H–3 and H–4 (12.4 Hz for trans-42 and 6.7 Hz for cis-42).

To investigate if less acidic isocyanoacetates would also react with in situ generated

azadienes, methyl isocyanoacetate 41 was tested. Application of 41 under standard reaction conditions gave the expected dihydropyridone 42 in only 19% as a mixture of diastereomers (trans:cis = 67:33). Besides 42, dihydropyridone 44 was isolated in 18% yield after flash column chromatography. We reasoned that the initially formed product 42

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138

undergoes a fast reaction with azadiene 15 that is still present in the reaction mixture (Scheme 3). Hydrolysis of the resulting imine 43 during workup/purification affords ketone 44. Formation of 44 was completely prevented using a reverse addition strategy. Slow addition of the in situ generated azadiene to a solution of methyl isocyanoacetate 41 gave dihydropyridone 42 as a 63:37 mixture in 32% (Table 2, entry 5). Although the yield is still moderate, this result suggests that also isocyanoacetates lacking additional electron withdrawing α-substituents might be sufficiently reactive in cycloadditions with azadienes, which would mean a further broadening of the reaction scope. Several isocyanides based on α-amino acids are currently under investigation.

Scheme 3

NHPh

PMP

NH

O

PMP

Ph

1542

+NC

NH

O

PMP

Ph

43

NC PMP

Ph

NH

NH

O

PMP

Ph

44

NC PMP

Ph

OH2O

6.3 Mechanistic Consideration

The isolation of unexpected product 44 indicates that azadienes 6 can undergo Michael attack by α-isocyano carbanions. Thus, most likely, the mechanism of the formation of 3,4-dihydro-2-pyridones 48 from in situ generated azadienes 6 involves a Michael-type attack of the deprotonated isocyanoacetate 46 to form tentative intermediate 47 and subsequent lactamisation (Scheme 4). The stereocentres at C–3 and C–4 are formed during the formation of the bond between the α-carbon of the isocyanoacetate 45 and the C–4 of 6.

Scheme 4

NHR1

R2

NH

O

R2

R1

6 48

+ NCR3

R3

CO2MeCN

R3

CO2MeCNN

O

R2

R1

47

NCR3

OMeHNHR1

R2

6

−H+ −MeO−

+H+

4645

With the exception of 42, all dihydropyridones were formed with complete diastereoselectivity regarding the stereocentres at C–3 and C–4. Spartan DFT calculations (B3LYP 6–31G*) show that, in general, the thermodynamically more stable cis-diastereomers are formed (Table 3), although in some cases, the energy differences are within the margin of error (entries 1, 6 and 8). However, these figures do not account for the observed selectivities. In order to rationalise the remarkable diastereoselectivity, the mechanism of the reaction between isocyanoacetates 45 and azadienes 6 should be studied, for example using computational chemistry.


139

Table 3. Calculated distances between Ha and Hb in 3,4-cis-dihydro-2-pyridones (Rcis) and in 3,4-trans-dihydro-2-pyridones (Rtrans) and energy differences between 3,4-trans- and 3,4-cis-dihydro-2-pyridones ΔE(trans)−(cis)

a

entry compound rtrans (Ǻ) rcis (Ǻ) ΔE(trans)−(cis) (kcal mol−1)

1 17 4.195 2.128 −0.1 2 19 3.789 2.122 2.5 3 21 3.097 2.474b 2.9 4 25 3.823 2.452 1.3 5 31 4.242 2.490 2.1 6 35 4.201 1.722 −0.3 7 37 3.781 2.138 2.6 8 39 3.793 2.154 0.1 9 40 4.197 2.159 2.5

a B3LYP (6–31G*). b In crystal structure (Figure 2): 2.50 Ǻ.

Initial Spartan semiempircal PM3 calculations (with R1=R2=R3=Ph) indicate that during

the attack of 46 to 6, the R2 and R3 groups are in close proximity, probably because this allows π-stacking of the two phenyl rings. Furthermore, the isocyano group of 46 is oriented in the ‘endo’ position of the azadiene 6, while the ester group points away from 6. Attack of 46 to 6 in this orientation indeed leads to the 3,4-cis-diastereomer 42. At the moment, the proposed reaction mechanism is under investigation using a more advanced computational setup. In order to give a quantitative explanation of the observed diastereoselectivity, activation barriers of the different reaction steps need to be calculated.

6.4 Conclusions

In a programme set up to generate scaffold diversity from in situ generated reactive intermediates (in this case, azadienes), a novel, highly diastereoselective multicomponent synthesis of 3,4-dihydro-2-pyridones was developed. The reaction works well with a wide range of substituents, although aliphatic and highly electron withdrawing aldehyde substituents are not suitable. Preliminary experiments show that also isocyanoacetates lacking an additional EWG can be applied. The free amido nitrogen and the isocyano group make the products excellent candidates for further derivatisation to diverse libraries of Freidinger-type β-turn mimics. Currently, the unprecedented 3-isocyano-3,4-dihydro-2-pyridones are being used in Passerini and Ugi reactions and the possibilities to develop new

Chapter 6

140

six- or seven-component reactions are under investigation. Furthermore, the reaction mechanism of the cycloaddition of isocyanoacetates to azadienes will be studied using DFT calculations.


Dr. Marek Smoluch (Vrije Universiteit Amsterdam) is gratefully acknowledged for conducting (HR)MS measurements. This work was partially supported (M.L., A.L.S.) by the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (CW-NWO).

6.6 Computational Details

DFT calculations were performed with the Spartan ’02 program for Windows,25 using Becke’s three-parameter hybrid exchange functional combined with the Lee-Yang-Parr correlation functional, denoted as B3LYP, and the 6–31G* basis set.


General Information: All reactions were carried out under an inert atmosphere of dry argon. Standard syringe techniques were applied for transfer of air sensitive reagents and dry solvents. Melting points were measured using a Stuart Scientific SMP3 melting point apparatus and are uncorrected. Infrared (IR) spectra were obtained from CHCl3 films on NaCl tablets (unless noted otherwise), using a Matteson Instuments 6030 Galaxy Series FT-IR spectrophotometer and wavelengths (ν) are reported in cm−1. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 (400.13 MHz and 100.61 MHz respectively), a Bruker Avance 250 (250.13 MHz and 62.90 MHz respectively) or a Bruker Avance 200 (200.13 MHz and 50.32 MHz respectively) with chemical shifts (δ) reported in ppm downfield from tetramethylsilane. Peak assignment was also done with the aid of gs-COSY, gs-HMQC and gs-HMBC measurements. Assignment of relative stereochemistry was achieved using gs-NOESY measurements. MS and HRMS spectra data were recorded on a Finnigan Mat 900 spectrometer. Chromatographic purification refers to flash chromatography using the indicated solvent (mixture) and Baker 7024-02 silica gel (40μ, 60 Å). Thin Layer Chromatography was performed using silica plates from Merck (Kieselgel 60 F254 on aluminium with fluorescence indicator. Compounds on TLC were visualised by UV-detection. THF was dried and distilled from sodium benzophenone ketyl prior to use. Benzonitrile was dried with MgSO4 and then distilled from P2O5 under reduced pressure. Other commercially available reagents were used as purchased. General Procedure I for the synthesis of dihydropyridones: All reactions were carried out at a concentration of 0.2 M of diethyl methylphosphonate 3, 0.24 M of n-BuLi, 0.22 M of nitrile, 0.22 M of aldehyde and 0.22 M of isocyanoacetate in dry THF. Always 1.0 mmol of the limiting reaction component (diethyl methylphosphonate 3) was used. 1.2 equiv. of n-BuLi (1.6 M solution in hexane) were added at –78 °C to a stirred solution of phosphonate in THF. After stirring at –78 °C for 1.5 h the nitrile (1.1 equiv.) was added and the mixture was then stirred at –78 °C for 45 min., at –40 °C for 1 h and at –5 °C for 30 min. The aldehyde (1.1 equiv.) was added and, after stirring at –5 °C for 30 min., the mixture was allowed to warm to rt and stirred for 1.5 h. Finally the isocyanoacetate (1.1 equiv.) was added and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the crude product purified by column chromatography.


141

Dihydropyridone 17. According to General Procedure I, reaction between phosphonate 3, n-BuLi, benzonitrile 13, p-anisaldehyde 14 and isocyanoacetate 16, followed by column chromatography (PE:EtOAc = 75:25 → EtOAc), afforded 17 (243 mg, 64%) as a yellow foam. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.53 (s, 1H), 7.47–7.34 (m, 10H), 7.04 (d, J = 8.7 Hz,

2H), 6.77 (d, J = 8.7 Hz, 2H), 5.66 (dd, J = 4.5, 1.7 Hz, 1H), 4.25 (d, J = 4.4 Hz, 1H), 3.75 (s, 3H); 13C NMR (50 MHz, CDCl3): δ (ppm) 165.8 (C), 162.8 (C), 160.0 (C), 137.3 (C), 135.8 (C), 133.9 (C), 130.9 (2×CH), 130.0 (CH), 129.5 (2×CH), 129.4 (CH), 129.0 (2×CH), 127.8 (C), 126.8 (2×CH), 125.6 (2×CH), 114.3 (2×CH), 105.9 (CH), 71.1 (C), 55.7 (CH3), 51.1 (CH); IR (KBr): 2127 (m), 1708 (s), 1528 (s), 1472 (m), 1264 (m); HRMS (EI, 70 eV): calculated for C25H20N2O2 (M+) 380.1525, found 380.1516; MS (EI, 70 eV): m/z (%) = 380 (61) [M+], 236 (100), 115 (8), 104 (10).

Dihydropyridone 19. According to General Procedure I, reaction between phosphonate 3, n-BuLi, benzonitrile 13, p-chlorobenzaldehyde 18 and isocyanoacetate 16, followed by column chromatography (c-hexane:EtOAc = 9:1 → 7:3), afforded 19 (250 mg, 72%) as a yellow foam. 1H NMR (250 MHz, CDCl3): δ (ppm) 7.61 (s, 1H), 7.49–7.39 (m, 10H), 7.23 (d, J = 8.5 Hz,

2H), 7.05 (d, J = 8.5 Hz, 2H), 5.64 (dd, J = 4.1, 1.3 Hz, 1H), 4.29 (d, J = 4.2 Hz, 1H); 13C NMR (63 MHz, CDCl3): δ (ppm) 165.0 (C), 162.8 (C), 137.5 (C), 134.8 (C), 134.3 (C), 134.1 (C), 133.3 (C), 130.6 (2×CH), 129.7 (CH), 129.10 (2×CH), 129.07 (CH), 128.59 (2×CH), 128.57 (2×CH), 126.3 (2×CH), 125.2 (2×CH), 104.6 (CH), 70.3 (C), 50.9 (CH); IR (neat): 2127 (w), 1699 (s), 1490 (m), 1092 (m), 1014 (m); HRMS (EI, 70 eV): calculated for C24H17ClN2O (M+) 384.1029, found 384.1027; MS (EI, 70 eV): m/z (%) = 384 (18) [M+], 356 (12), 293 (14), 242 (30), 241 (21), 240 (56), 234 (100), 175 (14), 149 (13), 115 (12), 105 (38), 104 (50), 77 (38).

Dihydropyridone 21. According to General Procedure I, reaction between phosphonate 3, n-BuLi, benzonitrile 13, benzaldehyde 20 and isocyanoacetate 16, followed by column chromatography (c-hexane:EtOAc = 9:1 → 7:3), afforded 21 (343 mg, 98%) as a yellow foam. Slow crystallisation from EtOAc/pentane afforded the pure product as pale yellow crystals. Mp

174–176 oC (decomposes); 1H NMR (250 MHz, CDCl3): δ (ppm) 8.34 (s, 1H), 7.47–7.19 (m, 15H), 5.72 (dd, J = 4.4, 1.2 Hz, 1H); 4.32 (d, J = 4.5 Hz, 1H); 13C NMR (63 MHz, CDCl3): δ (ppm) 165.2 (C), 162.4 (C), 137.0 (C), 135.6 (C), 135.2 (C), 133.4 (C), 129.6 (CH), 129.3 (2×CH), 129.1 (2×CH), 129.0 (CH), 128.5 (2×CH), 128.4 (2×CH), 128.3 (CH), 126.3 (2×CH), 125.2 (2×CH), 105.1 (CH), 70.4 (C), 51.4 (CH); IR (neat): 2129 (s), 1715 (s), 1683 (s), 1495 (s), 1455 (s), 1265 (s); HRMS (EI, 70 eV): calculated for C24H18N2O (M+) 350.1419, found 350.1405; MS (EI, 70 eV): m/z (%) = 208 (73), 207 (100), 206 (94), 191 (31), 179 (21), 165 (11), 147 (13), 131 (30), 119 (29), 115 (25), 105 (86), 104 (62), 103 (35). Crystals suitable for X-ray crystal structure determination were obtained by the slow diffusion of pentane into a saturated solution of 21 in THF.

Crystallographic Data for 21. C24H18N2O, Fw = 350.40, colourless triangular plate,

0.51 × 0.36 × 0.12 mm3, triclinic, P 1 (no. 2), a = 7.2566(2), b = 8.17547(18), c =

16.3566(7) Å, α = 92.313(1), β = 100.627(1), γ = 103.381(1)°, V = 924.32(5) Å3, Z = 2, Dx = 1.259 g/cm3, μ = 0.08 mm-1. 23518 Reflections were measured on a Nonius Kappa CCD diffractometer with rotating anode (graphite monochromator, λ = 0.71073 Å) up to a resolution of (sin θ/λ)max = 0.65 Å–1 at a temperature of 110 K. The reflections were

corrected for absorption and scaled on the basis of multiple measured reflections with the program SADABS26 (0.85−1.00 correction range). 4258 Reflections were unique (Rint = 0.0259). The structure was solved with Direct Methods27 and refined with SHELXL-9728 against F2 of all reflections. Non hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms were located in the difference Fourier map. The N–H hydrogen atom was refined freely with isotropic displacement parameters; all other hydrogen atoms were refined with a riding model. 248 Parameters were refined with no restraints. R1/wR2 [I > 2σ(I)]: 0.0437/0.1015. R1/wR2 [all reflections]: 0.0579/0.1100. S = 1.026. Residual electron density between −0.30 and 0.27 e/Å3. Geometry

NH

O

PMP

NC

Ph

Ph

N1

2345

6NH

ON2

O1

1

78

9

1011

1213

14

15

16

17

18

1920

21

2223

24

N C

NH

O

PCP

NC

Ph

Ph

NH

O

Ph

NC

Ph

Ph

Chapter 6

142

calculations and checking for higher symmetry was performed with the PLATON program.29 CCDC 612759 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Table 4. Selected bond distances (Å) in the crystal structure of 20. Standard uncertainties are given in parentheses.

C2-O7 1.2248(18) C5-C6 1.3394(16) N1-C2 1.3448(19) C6-N1 1.4174(18) C2-C3 1.5601(16) C3-N8 1.4501(16) C3-C4 1.5605(16) N8-C9 1.1580(19) C4-C5 1.5068(17)

Table 5. Selected bond angles (º) in the crystal structure of 20. Standard uncertainties are given in parentheses.

N1-C2-C3 116.13(12) C3-C2-O7 120.23(12) C2-C3-C4 108.38(9) N1-C2-O7 123.59(11) C3-C4-C5 109.84(10) C2-C3-N8 104.32(10) C4-C5-C6 121.70(12) C4-C3-N8 109.20(10) C5-C6-N1 118.12(12) C3-N8-C9 177.77(15) C6-N1-C2 125.46(11)

Table 6. Hydrogen bonding geometry in the crystal structure of 20. Standard uncertainties are given in parentheses.a

D-H…A D-H (Å) H…A (Å) D….A (Å) D-H…A (º)

N1-H1…O7i 0.887(19) 2.009(19) 2.8821(14) 167.9(16) a Symmetry operation i: 1-x, 1-y, 1-z..

Dihydropyridone 25. According to General Procedure I, reaction between phosphonate 3, n-BuLi, benzonitrile 13, 5-methylfurfural 24 and isocyanoacetate 16, followed by column chromatography (c-hexane:EtOAc = 9:1 → 4:6), afforded 25 as a yellow foam (128 mg, 36%). 1H NMR (250 MHz, CDCl3): δ (ppm) 8.17 (s, 1H), 7.55–7.38 (m, 10H), 6.18 (d, J = 2.6 Hz, 1H), 5.90 (s, 1H), 5.57 (d, J = 5.4 Hz, 1H), 4.40 (d, J = 5.4 Hz, 1H), 2.20 (s, 3H); 13C NMR (63 MHz): δ (ppm) 165.2 (C), 161.5 (C), 152.7 (C), 147.2 (C), 137.2 (C), 135.0 (C), 133.3 (C),

129.5 (CH), 129.2 (CH), 128.9 (2×CH), 128.7 (2×CH), 125.9 (2×CH), 125.1 (2×CH), 110.0 (CH), 106.4 (CH), 102.1 (CH), 69.1 (C), 45.1 (CH), 13.4 (CH3); IR (neat): 2128 (s), 1693 (s), 1449 (s); HRMS (EI, 70 eV): calculated for C23H18N2O2 (M+) 354.1368, found 354.1356; MS (EI, 70 eV): m/z (%) = 354 (42) [M+], 326 (12), 312 (30), 234 (79), 212 (100), 197 (98), 168 (22), 153 (8), 141 (17), 115 (15), 77 (23).

Dihydropyridone 31. According to General Procedure I, reaction between phosphonate 3, n-BuLi, benzonitrile 13, 1-cyclohexene-1-carboxaldehyde 30 and isocyanoacetate 16, followed by column chromatography (c-hexane:EtOAc = 85:15 → 7:3), afforded 31 as a yellow solid (227 mg, 64%). Mp 142–145 ºC (decomposes); 1H NMR (250 MHz, CDCl3): δ (ppm) 8.21 (s, 1H), 7.61–7.35 (m, 10H), 5.83 (br s, 1H), 5.41 (d, J = 6.0 Hz, 1H), 3.62 (d, J = 6.0 Hz, 1H), 2.19–1.51 (m, 8H); 13C NMR (63 MHz, CDCl3): δ (ppm) 165.9 (C), 160.7 (C), 136.3 (C), 136.2 (C),

134.1 (C), 133.5 (C), 129.4 (CH), 129.1 (CH), 129.02 (2×CH), 129.96 (CH), 128.8 (2×CH), 125.7 (2×CH), 124.9 (2×CH), 103.4 (CH), 68.7 (C), 54.0 (CH), 25.6 (CH2), 25.3 (CH2), 22.7 (CH2), 21.9 (CH2); IR (neat): 2141 (s), 1691 (s); HRMS (EI, 70 eV): calculated for C24H22N2O (M+) 354.1732, found 354.1714; MS (EI, 70 eV): m/z (%) = 354 (44) [M+], 325 (16), 282 (23), 234 (42), 210 (15), 195 (100), 182 (31), 175 (14), 116 (18), 105 (93), 77 (29).

NH

O

O

NC

Ph

Ph

NH

O

NC

Ph

Ph


143

Dihydropyridone 33. According to General Procedure I, reaction between phosphonate 3, n-BuLi, benzonitrile 13, (1R)-(−)-myrtenal 32 and isocyanoacetate 16, followed by column chromatography (c-hexane:EtOAc = 85:15 → 7:3), afforded 33 as a 1:1 mixture of two diasteroisomers as a yellow foam (304 mg, 77%). 1H NMR (250 MHz, CDCl3): δ (ppm) 8.19 (s, 1H), 8.08 (s, 1H), 7.61–7.35 (m, 10H + 10H), 5.67 (s, 1H), 5.52 (s, 1H), 5.41 (s, 1H), 5.31 (s, 1H), 3.80–3.74 (m, 1H + 1H), 2.49–2.06 (m, 5H + 5H), 1.28–1.19 (m, 4H + 4H), 0.89 (s, 3H),

0.85 (s, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 165.6 (C), 165.5 (C), 162.0 (C), 161.5 (C), 142.7 (C), 142.0 (C), 136.4 (C), 136.3 (C), 136.2 (C), 135.7 (C), 133.8 (C), 133.6 (C), 129.45 (CH), 129.39 (CH), 129.1 (2×CH), 129.0 (2×CH + 1×CH), 128.7 (2×CH), 128.6 (2×CH), 126.6 (CH), 126.1 (2×CH), 125.7 (2×CH), 125.04 (2×CH), 124.98 (2×CH), 124.2 (CH), 123.7 (CH), 104.2 (CH), 102.5 (CH), 69.0 (C), 68.5 (C), 53.0 (CH), 51.1 (CH), 47.2 (CH), 43.6 (CH), 40.4 (CH), 40.2 (CH), 37.9 (C), 37.8 (C), 32.3 (CH2), 31.9 (CH2), 31.7 (2×CH2), 26.2 (2×CH3), 21.7 (CH3), 21.4 (CH3); IR (neat): 2141 (s), 1697 (s), 1693 (s), 1451 (s), 1254 (s), 1214 (s); HRMS (EI, 70 eV): calculated for C27H26N2O (M+) 394.20.45, found 394.2026; MS (EI, 70 eV): m/z (%) = 394 (14) [M+], 351 (11), 325 (16), 235 (14), 175 (17), 130 (14), 116 (50), 105 (29), 90 (35), 83 (100), 77 (24), 59 (14).

Dihydropyridone 35. According to General Procedure I, reaction between phosphonate 3, n-BuLi, i-butyronitrile 34, p-anisaldehyde 14 and isocyanoacetate 16, followed by column chromatography (c-hexane:EtOAc = 7:3), afforded 35 (197 mg, 57%) as a yellow foam. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.95 (s, 1H), 7.40–7.34 (m, 5H), 6.99 (d, J = 8.7 Hz, 2H),

6.75 (d, J = 8.8 Hz, 2H), 5.10 (dd, J = 2.7, 1.0 Hz, 1H), 4.02 (d, J = 4.2 Hz, 1H), 3.75 (s, 3H), 2.40 (m, 1H), 1.11 (d, J = 6.3 Hz, 6H); 13C NMR (50 MHz, CDCl3): δ (ppm) 165.5 (C) 161.2 (C), 159.2 (C), 142.6 (C), 135.5 (C), 130.2 (2×CH), 128.2 (CH), 127.84 (2×CH), 127.76 (C), 126.2 (2×CH), 113.6 (2×CH), 101.6 (CH), 70.6 (C), 55.2 (CH3), 49.9 (CH), 31.2 (CH), 20.0 (CH3), 20.0 (CH3); IR (KBr): 2127 (m), 1708 (s), 1513 (m), 1458 (s), 1250 (m); HRMS (EI, 70 eV): calculated for C22H22N2O2 (M+) 346.1618, found 346.1678; MS (EI, 70 eV): m/z (%) = 346 (100) [M+], 331 (9), 303 (18), 202 (80).

Dihydropyridone 37. According to General Procedure I, reaction between phosphonate 3, n-BuLi, 2-furonitrile 36, p-anisaldehyde 14 and isocyanoacetate 16, followed by column chromatography (c-hexane:EtOAc = 85:15 → 7:3), afforded 37 as a red oil (282 mg, 76%). 1H NMR (250 MHz, CDCl3): δ (ppm) 9.41 (s, 1H), 7.52–7.38 (m, 6H), 7.12 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 3.4 Hz, 1H), 6.39 (d, J = 1.6 Hz, 1H), 5.87 (d, J =

4.8 Hz, 1H), 4.29 (d, J = 4.8 Hz, 1H), 3.76 (s, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 165.5 (C), 162.0 (C), 159.49 (C), 146.3 (C), 143.1 (CH), 135.4 (C), 130.3 (2×CH), 129.0(CH), 128.6 (2×CH), 128.0 (C), 127.3 (C), 126.2 (2×CH), 113.8 (2×CH), 111.7 (CH), 107.3 (CH), 102.5 (CH), 70.6 (C), 55.1 (CH3), 50.2 (CH); IR (neat): 2129 (m), 1699 (s), 1511 (s), 1256 (m); HRMS (EI, 70 eV): calculated for C23H18N2O3 (M+) 370.1317, found 370.1307; MS (EI, 70 eV): m/z (%) = 370 (100) [M+], 341 (42), 226 (54), 224 (52), 197 (14), 135 (24), 105 (12).

Dihydropyridone 39. According to General Procedure I, reaction between phosphonate 3, n-BuLi, benzonitrile 13, p-anisaldehyde 14 and isocyanoacetate 38, followed by column chromatography (c-hexane:EtOAc = 8:2 → 6:4), afforded 39 as a yellow solid (249 mg, 60%). Mp 187–190 ºC (decomposes); 1H NMR (250 MHz, DMSO-d6): δ (ppm) 10.62 (s, 1H), 7.60 (d,

J = 8.7 Hz, 2H), 7.51–7.48 (m, 4H), 7.40–7.37 (m, 3H), 7.21 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.70 (d, J = 5.5 Hz, 1H), 4.55 (d, J = 5.6 Hz, 1H), 3.31 (s, 3H); 13C NMR (63 MHz, CDCl3): δ (ppm) 164.5 (C), 163.1 (C), 159.7 (C), 136.9 (C), 135.0 (C), 133.6 (2×C), 130.4 (2×CH), 129.9 (CH), 129.3 (2×CH), 128.7 (2×CH), 128.0 (2×CH), 127.0 (C), 125.2 (2×CH), 113.9 (2×CH), 105.8 (CH), 70.2 (C), 55.3 (CH3), 50.9 (CH). IR (neat): 2126 (s), 1733 (s), 1716 (s); HRMS (EI, 70 eV): calculated for C25H19ClN2O2 (M+) 414.1135, found 414.1141; MS (EI, 70 eV): m/z (%) = 414 (8) [M+], 296 (82), 251 (31), 248 (56), 236 (41), 221 (35), 195 (52), 152 (62), 137 (100), 135 (68), 105 (54), 77 (41), 57 (27).

NH

O

NC

Ph

Ph

NH

O

PMP

NCPh

NH

O

PMP

NCPh

O

NH

O

PMP

NCPCP

Ph

Chapter 6

144

Dihydropyridone 40. According to General Procedure I, reaction between phosphonate 3, n-BuLi, benzonitrile 13, benzaldehyde 20 and isocyanoacetate 38, followed by column chromatography (c-hexane:EtOAc = 8:2 → 7:3), afforded 40 as a yellow solid (231 mg, 60%). Mp 150–154 ºC (decomposes); 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.66 (s, 1H), 7.60 (d,

J = 8.5 Hz, 2H), 7.54–7.49 (m, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.40–7.38 (m, 3H), 7.36–7.28 (m, 5H), 5.73 (d, J = 5.4 Hz, 1H), 4.61 (d, J = 5.4 Hz, 1H), 3.31 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ (ppm) 164.0 (C), 161.0 (C), 137.5 (C), 136.0 (C), 134.9 (C), 133.7 (C), 133.3 (C), 129.2 (2×CH), 129.0 (CH), 128.58 (2×CH), 128.55 (2×CH), 128.3 (2×CH), 128.2 (2×CH), 128.0 (CH), 125.6 (2×CH), 104.8 (CH), 69.6 (C), 48.5 (CH); IR (KBr): 2125 (m), 1693 (s); HRMS (EI, 70 eV): calculated for C24H17ClN2O (M+) 384.1029, found 384.1034; MS (EI, 70 eV): m/z (%) = 384 (27) [M+], 356 (17), 268 (63), 206 (100).

Dihydropyridone 42. 1.2 equiv. of n-BuLi (1.6 M solution in hexane) were added at –78 °C to a stirred solution of phosphonate 3 (1 mmol, 153 mg) in THF (5 mL). After stirring at –78 °C for 1.5 h benzonitrile 13 (1.1 mmol, 113 mg) was added and the mixture was then stirred at –78 °C for 45 min., at –40 °C for 1 h and at –5 °C for 30 min. Then, p-anisaldehyde 14 (1.1 mmol, 150

mg) was added and, after stirring at –5 °C for 30 min., the mixture was allowed to warm to rt and stirred for 1.5 h. The reaction mixture was slowly added to a solution of isocyanoacetate 41 (1.1 mmol, 109 mg) in 0.5 mL THF via a syringe. The reaction mixture was stirred for 18 h at rt and concentrated in vacuo. Purification of the crude product by column chromatography (c-hexane:EtOAc = 17:3 → 6:4) afforded 42 as a pale yellow foam (97 mg, 32%, trans:cis = 63:37). 1H NMR (400 MHz, CDCl3, 45 ºC): δ (ppm) 7.71 (br s, 1H + 1H), 7.50–7.40 (m, 5H + 5H), 7.29–7.23 (m, 2H + 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.66 (dd, J = 5.8, 1.5 Hz, 1H), 5.47 (dd, J = 2.7, 1.7 Hz, 1H), 4.77 (d, J = 6.7 Hz, 1H), 4.45 (d, J = 12.4 Hz, 1H), 4.21–4.02 (m, 1H + 1H), 3.81 (s, 3H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3, 45 ºC): δ (ppm) 163.2 (C), 162.9 (C), 162.8 (C), 162.0 (C), 159.9 (C), 159.7 (C), 137.5 (C), 137.1 (C), 133.7 (C), 133.6 (C), 130.5 (C), 129.8 (2×CH), 129.7 (2×CH), 129.20 (CH + CH), 129.18 (2×CH), 129.1 (2×CH), 126.6 (C), 125.2 (2×CH), 125.1 (2×CH), 114.7 (2×CH), 114.5 (2×CH), 105.4 (CH), 104.3 (CH), 60.2 (CH), 58.4 (CH), 55.4 (CH3), 55.3 (CH3), 45.4 (CH), 42.7 (CH); IR (neat): 2152 (s), 1697 (s), 1512 (m); HRMS (EI, 70 eV): calculated for C19H16N2O2 (M+) 304.1212, found 304.1207; MS (EI, 70 eV): m/z (%) = 303 (64). 289 (100), 257 (41), 170 (57).

Dihydropyridone 44. According to General Procedure I, reaction between phosphonate 3, n-BuLi, benzonitrile 13, p-anisaldehyde 14 and isocyanoacetate 41, followed by column chromatography (c-hexane:EtOAc = 8:2 → 7:3), afforded 42 as a yellow foam (58 mg, 19%, trans:cis = 67:33) together with 44 as a yellow oil (98 mg, 18%). 1H NMR (400 MHz,

CDCl3): δ (ppm) 7.92–7.89 (m, 2H), 7.58–7.46 (m, 4H), 7.45–7.29 (m, 7H), 7.00–6.98 (m, 2H), 6.91–6.87 (m, 2H), 6.80–6.77 (m, 2H), 5.57 (dd, J = 6.8, 1.6 Hz, 1H), 4.26 (t, J = 5.5 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.73 (d, J = 5.5 Hz, 2H), 3.34 (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 196.8 (C), 165.6 (C), 162.7 (C), 159.5 (C), 159.4 (C), 137.1 (C), 136.5 (C), 133.5 (C), 133.1 (CH), 130.0 (2×CH), 129.6 (CH), 129.4 (C), 129.1 (2×CH), 128.4 (2×CH), 128.0 (2×CH), 126.9 (C), 125.2 (4×CH), 114.1 (2×CH), 114.0 (2×CH), 103.6 (CH), 74.2 (C), 55.1 (CH3), 55.1 (CH3), 45.9 (CH), 42.7 (CH), 40.5 (CH2); IR (neat): 2135 (m), 1693 (s), 1683 (s), 1511 (s); HRMS (EI, 70 eV): calculated for C35H30N2O4 (M+) 542.2206, found 542.2199; MS (EI, 70 eV): m/z (%) = 542 (0.5), 303 (42), 238 (100), 161 (88).


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[11] Yu, K.-L.; Rajakumar, G.; Srivastava, L. K.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1988, 31, 1430–1436.

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[13] Glasnov, T. N.; Vugts, D. J.; Koningstein, M. M.; Desai, B.; Fabian, W. M. F.; Orru, R. V. A.; Kappe, C. O. QSAR Comb. Sci. 2006, 25, 509–518.

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[15] Eisenbraun, E. J.; Sullins, D. W.; Browne, C. E.; Shoolery, J. N. J. Org. Chem. 1988, 53, 3968–3972. [16] Amat, M.; Llor, N.; Huguet, M.; Molins, E.; Espinosa, E.; Bosch, J. Org. Lett. 2001, 3, 3257–3260. [17] Bach, T.; Bergmann, H.; Brummerhop, H.; Lewis, W.; Harms, K. Chem. Eur. J. 2001, 7, 4512–4521. [18] a) Ochoa, E.; Suarez, M.; Verdecia, Y.; Pita, B.; Martin, N.; Quinteiro, M.; Seoane, C.; Soto, J. L.; Duque, J.;

Pomes, R. Tetrahedron 1998, 54, 12409–12420. b) Rodríguez, H.; Suarez, M.; Pérez, R.; Petit, A.; Loupy, A. Tetrahedron Lett. 2003, 44, 3709–3712.

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Chapter 7

Retrospection and Outlook

This thesis deals with the development of new multicomponent reactions with α-acidic isocyanides and the application of such MCRs for the synthesis of new NHC complexes and potential p53-MDM2 interaction inhibitors. In this Chapter, the different projects described in Chapters 2–6 are evaluated and possible topics for further investigation are indicated.

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148

7.1 Multicomponent Synthesis of 2H-2-Imidazolines

A versatile MCR leading to a wide range of 2H-2-imidazolines has been developed (Chapters 2 and 3). The variability with respect to the amine and aldehyde components in this reaction proved very high. Although already 4 different isocyanides can be used (Chapters 2, 3 and 5), the variability of this third component is still somewhat limited. Application of less acidic isocyanides, for example α-isocyanoacetates derived from amino acids other than phenylglycine (Chart 1),1 should be possible with modified reaction conditions, like different solvents, higher temperatures or the use of (silver) catalysis.

Chart 1

Application of chiral amine and aldehyde inputs in the MCR does lead to some chiral induction (Chapter 3). However, this approach limits the exploratory power of the reaction. The use of transition metal catalysis in combination with chiral ligands would be a more elegant strategy to generate the 2-imidazolines stereoselectively.

The combination of MCRs between amines 6, aldehydes 7 and p-nitrobenzyl isocyanide

8 and post-MCR oxidative conditions could be developed as an easy and atom efficient method for the generation of new imidazoles 9 under mild conditions (Scheme 1). This method would be complementary to the TosMIC based MCR published by Sisko.2

Scheme 1

Finally, the strategic choice of substituents on the input components could allow MCRs combined with in situ ring closure reactions like Diels-Alder reactions, ring closing metathesis (RCM), lactamisations or Heck reactions, quickly leading to scaffold diversity. Two examples involving a MCR-RCM approach are depicted in Scheme 2. The sensitive β,γ-unsaturated aldehydes 11 can be prepared by the oxidation of the corresponding alcohols 10.3


149

Scheme 2

7.2 N-Heterocyclic Carbenes

The multicomponent synthesis of 2-imidazolines has been successfully applied for the generation of unprecedented types of NHC complexes of rhodium and iridium. The substituents on all positions of the NHC ligand can be varied easily. However, the synthesis and isolation of free carbenes via this route remains to be achieved. The availability of free NHCs would facilitate (in situ) preparation of NHC complexes of many different transition metals in order to test the ligands for a wide range of transition metal catalysed reactions. Also the dimerisation behaviour of various unsymmetrically substituted NHCs could be further explored. One possible route towards free NHCs 22 involves the reduction of thioureas 21 that can be formed by the reaction of in situ generated NHCs with elemental sulfur (Scheme 3).

Scheme 3

7.3 C–2 Functionalisation of 2H-2-Imidazolines

Application of methyl 2-(p-chlorophenyl)-2-isocyanoacetate in our multicomponent synthesis gives access to 2-imidazolines containing Nutlin-like backbones (Chapter 5). C–2 arylation of these 2H-2-imidazolines can be achieved in 5 steps. An alkylation, oxidation, deprotection and thionation sequence provides Liebeskind-Srogl precursors with either a C–4 or a C–5 ester group in very high yields. Microwave assisted, palladium catalysed coupling of these cyclic thioureas with aryl boronic acids affords C–2 arylated imidazolines. What remains to be done is the incorporation of ortho-substituted aryl rings at C–2 and the biological evaluation of the potential p53-MDM2 interaction inhibitors.

Chapter 7

150

Although the suitability of this protocol to arrive at Nutlin analogues has been proven, some improvements can be envisioned. Choice of appropriate, easily removable protective groups at the N–1 or the N–3 of the imidazolinium salts could shorten the route to the Liebeskind-Srogl precursors (Scheme 4). Furthermore, this shortcut would prevent the mCPBA mediated oxidation and the thionation step with Lawesson’s reagent, the least atom efficient reactions in our protocol. However, the most desirable procedure for the synthesis of Nutlin analogues still involves the direct C–2 arylation of 2H-2-imidazolines, which proved unsuccessful yet.

Scheme 4

Finally, the cyclic (thio)ureas that were synthesised with our MCR could give access to 2-aminoimidazolines, which are also biologically prevalidated scaffolds (Scheme 5).4

Scheme 5

7.4 Multicomponent Synthesis of 3,4-Dihydro-2-pyridones

Using a highly diastereoselective MCR between methyl diethylphosphonate, nitriles, aldehydes and α-isocyanoacetates, 3,4-dihydro-2-pyridones containing a 3-isocyano group can be generated efficiently (Chapter 6). The variability of the nitriles and aldehydes has been shown, but the application of isocyanoacetates lacking an additional withdrawing group (see for example Chart 1) should be investigated in more detail. Furthermore, employment of the complex isocyanides in additional MCRs, combined with derivatisation at N–1, could give access to new possible β-turn mimics (Scheme 6).

Scheme 6


151


[1] These are just 5 of the many α-isocyanoacetates available from Priaton (www. Priaton.de). [2] Sisko, J.; Kassick, A.J.; Mellinger, M.; Filan, J.J.; Allen, A.; Olsen, M.A. J. Org. Chem. 2000, 65,

1516−1524. [3] Vugts, D. J.; Veum, L.; Al-Mafraji, K.; Lemmens, R.; Schmitz, R. F.; de Kanter, F. J. J.; Groen, M. B.;

Hanefeld, U.; Orru, R. V. A. Eur. J. Org. Chem. 2006, 1672–1677. [4] Dardonville, C.; Rozas, I. Med. Res. Rev. 2004, 24, 639–661.

Summary

152

Summary

Currently, one of the key issues in medicinal chemistry is the development of new, rapid and clean methods for the synthesis of focused libraries of diversely substituted heterocycles. The most efficient strategies to quickly generate molecular complexity and diversity involve multicomponent reactions (MCRs), which are defined as one-pot reactions in which three or more components react to form a single product, incorporating essentially all atoms of the starting materials. Because of their one-pot character, atom efficiency and their possibility to employ readily available building blocks, MCRs approach the concept of Ideal Synthesis. Consequently, the design and development of (new) MCRs for the generation of heterocycles receives growing interest.

This thesis deals with the development and application of new MCRs that employ the

α-acidic character of isocyanides for the formation of versatile heterocyclic scaffolds. Some important topics in this thesis, MCRs, isocyanides and 2-imidazolines are briefly introduced in Chapter 1.

Multicomponent synthesis of 2H-2-imidazolines

The 2-imidazoline scaffold has been widely applied in medicinal chemistry and catalysis. Therefore, both fields of research would benefit from simple and flexible 2-imidazoline syntheses, which facilitate fast and efficient generation of diverse libraries of these compounds for high-throughput screening procedures. In Chapter 2 of this thesis, the development of a MCR towards 2-imidazolines of type 6 is described. This MCR proceeds through in situ formation of imines 3 from amines 1 and aldehydes 2, followed by attack of the isocyanoacetate 4 and subsequent ring closure (Scheme 1). Traces of amine present in the reaction mixture may act as basic catalyst to promote aldol type addition to generate the tentative intermediate 5.

Scheme 1

Summary

153

Although the application of the most simple isocyanoacetate (4a, R3 = H) did not give satisfying results, the somewhat more reactive methyl 2-phenylisocyanoacetate (4b, R3 = Ph), which can be easily synthesised from phenylglycine in three steps, provides 2-imidazolines 6 in moderate to very high yields in a one-pot, three component synthesis. In both the amine and the aldehyde components, a wide variety of aliphatic, aromatic, heteroaromatic and olefinic substituents is allowed. Diastereomeric ratios range from 1.5:1 to 4:1, always in favour of the isomers with R2 and R3 cis to each other. The reaction works well in MeOH, DCM or toluene, but gives poor yields when performed in THF. The bulkiness of the amine and aldehyde substituents plays a major roll in the performance of the MCR: Only one sterically demanding group (R2 or R3 = tBu or mesityl) is allowed.

In order to broaden the scope of our MCR, the application of other isocyanides

containing acidic α-protons was investigated (Chapter 3). The easily obtainable 9-isocyanofluorene 7 reacts with in situ formed imines to give spiro-2-imidazolines 8 (Scheme 2). Again, a wide variety of amine and aldehyde substituents proved applicable. Even bis-amines and bis-aldehydes were employed to synthesise bis-imidazolines.

Scheme 2

Although p-nitrobenzyl isocyanide 9 does normally not react with in situ formed imines, not even at elevated temperatures, the addition of only 2 mol% AgOAc leads to good yields of 4-monosubstituted 2-imidazolines 10 (Scheme 2). When R3 = H, both diastereomers of the products are oxidised by air to form imidazoles 11, although at different rates. DFT calculations have provided a plausible explanation for the rate difference of these (probably radical mediated) oxidations.

Also allyl isocyanide was tried as isocyanide component in our MCR, but in spite of the

many conditions and catalysts tried, this remained without success. To rationalise the differences in reactivity of the various isocyanides in our MCR, DFT calculations proved helpful. Three factors play a role: 1) the proton affinity of the isocyanide (or isocyanide-silver complex); 2) the energy of the HOMO of the anion of the isocyanide; 3) the contribution of carbanion (pz) orbital in the HOMO.

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154

Finally, instead of aldehydes, ketones were tested as the oxo-components in the MCR. Although initially no product formation was seen, also here AgOAc proved to be a suitable catalyst.

Synthesis of novel NHC complexes

Several procedures for the synthesis of N-heterocylic carbenes (NHCs) have been reported. However, not many routes towards NHCs with non-identical C–4 and C–5 substituents are known. One example is the one-pot synthesis of thioureas followed by reduction with K or Na/K alloy as reported by Hahn. The method appears to be very successful when aliphatic side groups are used, but aromatic and even more delicate substituents do not survive the harsh reaction conditions. Since the alkylation and subsequent deprotonation of 2-imidazolines is an elegant and established route towards saturated NHCs, the above described multicomponent synthesis of 2-imidazolines was used to generate precursors for unprecedented types of NHCs (Chapter 4).

The first experiments were performed with imidazoline 12 containing the spiro-fluorenyl

group at C–4 and two protons at C–5, in order to prevent formation of diastereomeric mixtures (for example in case of dimerisation), which simplifies NMR analysis. As N–1 substituent, a tBu group was chosen, because it is known that bulky nitrogen substituents can prevent NHC dimerisation.

Scheme 3

Alkylation of 12 with methyl iodide gives the imidazolinium salt 13 in nearly quantitative yield. Deprotonation of 13 using sodium hydride never afforded an isolable, free NHC. Presumably, the dimerisation is catalysed by the imidazolinium salt itself. Deprotonation of imidazolinium salt 13 with KOtBu in the presence of a coordinatively unsaturated Rh complex gives Rh-NHC complex 14 in high yield (Scheme 3). Addition of excess KI to the reaction mixture ensures complete conversion to the iodo complex. Purification of 14 can be done with flash column chromatography. Ultimate structural evidence was obtained using XRD analysis.

Then, all substituents on the imidazolinium salts, the transition metal and ligands were

varied to prove the versatility of the method. Further, instead of a transition metal, also

Summary

155

elemental sulfur is a good NHC trapping agent. In total, 19 new NHC complexes were synthesised. A selection is shown in Chart 1. The properties of the carbene ligands were compared using XRD, IR and NMR analysis.

Chart 1

Synthesis of Nutlin analogues by the C–2 functionalisation of 2H-2-imidazolines

Inhibition of the interaction between the p53 tumour suppressor and its natural inhibitor MDM2 with small molecules is considered an effective strategy for cancer treatment (Chapter 5). Recently, a class of 2,4,5-triaryl-2-imidazolines called Nutlins has been identified as potent MDM2 inhibitors. We used the MCR between amines, aldehydes and methyl 2-(p-chlorophenyl)-2-isocyanoacetate to synthesise imidazolines with a Nutlin-like backbone 19 (Scheme 4).

The only known methods for the functionalisation of the C–2 of 2H-2-imidazolines

involve deprotonations with organolithium reagents, which is detrimental to the delicate functional groups in our molecules. Therefore we started a program to develop a mild method for the C–2 arylation of 2H-2-imidazolines. The trapping of in situ generated NHCs with elemental sulfur at room temperature was envisioned as the key step, since thioureas and isothioureas are known to undergo Liebeskind-Srogl cross coupling reactions with aryl or vinyl boronic acids (and stannanes).

Scheme 4

Unfortunately, direct cleavage of a p-methoxybenzyl (PMB) group from N–1 of thioureas could not be performed. Therefore, another method was developed. Oxidation of 2-

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156

imidazolinium salts with mCPBA affords imidazolidin-2-ones 20 in good yields. Cleavage of the PMB group in refluxing TFA and subsequent thionation of the resulting 1H- or 3H-imidazolidin-2-ones with Lawesson’s reagent affords the arylation precursors 21a and 21b in very high yields. Liebeskind-Srogl coupling under microwave irradiation (Kappe modification) gives the desired 2-aryl-2-imidazolines 22a and 22b in moderate (unoptimised) yields.

Multicomponent synthesis of 3,4-dihydro-2-pyridones

In order to further explore the potential of isocyanides with acidic α-protons, MCRs between methyl diethylphosphonate 23, nitriles 24, aldehydes 2 and isocyanoacetates 4 were examined (Chapter 6). To our surprise, these reactions did not lead to 5-vinyl substituted 2-imidazolines, but to unprecedented 3-isocyano-3,4-dihydro-2-pyridones 26 (Scheme 5).

Scheme 5

Apparently, 1,4-attack of the α-carbon of the (deprotonated) isocyanoacetates to the intermediate azadiene 25 is followed by lactamisation. This novel MCR is flexible with respect to the nitrile, aldehyde and isocyanoacetate substituents, although aliphatic and highly electron withdrawing aldehyde substituents are not suitable. At the moment, best results are obtained using 2-aryl substituted isocyanoacetates (which also give complete diastereoselectivity), but preliminary experiments show that also isocyanoacetates lacking an additional EWG can be applied. The beauty of the reaction lies in the fact that the products still contain the very versatile isocyano group. This feature, combined with the free amido nitrogen, make the products excellent candidates for further derivatisation to diverse libraries of Freidinger-type β-turn mimics via additional MCRs.

Outlook

In the last Chapter of this thesis (Chapter 7), the different projects described in Chapters 2–6 are evaluated and possible topics for further investigation are indicated.

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Samenvatting

Ontwikkeling en toepassing van nieuwe multicomponentenreacties met

α-zure isocyanides

In de hedendaagse speurtocht naar nieuwe geneesmiddelen is de ontwikkeling van

nieuwe, snelle en schone methoden voor de gerichte synthese van bibliotheken van divers gesubstitueerde heterocyclische verbindingen onontbeerlijk. De meest efficiënte strategieën voor de snelle introductie van moleculaire complexiteit en diversiteit maken gebruik van multicomponentenreacties (MCRs). MCRs zijn gedefinieerd als één-pots-reacties waarin drie of meer componenten met elkaar reageren tot een enkel reactieproduct dat zo goed als alle atomen van de startmaterialen bevat. MCRs benaderen het concept van de Ideale Synthese vanwege hun één-pots-karakter, atoomefficiëntie, en mogelijkheden tot het gebruik van algemeen beschikbare uitgangsstoffen. De interesse in het ontwerp en de ontwikkeling van (nieuwe) MCRs neemt logischerwijs gestaag toe.

In dit proefschrift is de ontwikkeling en toepassing van nieuwe MCRs beschreven. In

deze MCRs wordt gebruik gemaakt van het zure karakter van de α-protonen van isocyanides om veelzijdige heterocyclische verbindingen te construeren. Hoofdstuk 1 bevat een korte inleiding over enkele belangrijke onderwerpen in dit proefschrift: MCRs, isocyanides en 2-imidazolines.

Multicomponentsynthese van 2H-2-imidazolines

Het 2-imidazoline-basisskelet is terug te vinden in vele biologisch actieve verbindingen en in katalysatoren. Eenvoudige, flexibele 2-imidazolinesyntheses zijn interessant voor zowel farmaceuten als wetenschappers die zich bezighouden met katalyse, omdat deze methoden de snelle synthese van imidazolinebibliotheken voor high-throughput screening mogelijk maken. In Hoofdstuk 2 van dit proefschrift wordt de ontwikkeling van een MCR die leidt tot 2-imidazolines van type 6 beschreven. Deze MCR verloopt via de vorming van imines 3 uit amines 1 en aldehyden 2, gevolgd door de aanval van isocyanoacetaat 4 en ringsluiting (Schema 1). De aldolreactie die leidt tot het vermoedelijke intermediair zou gekatalyseerd kunnen worden door een spoortje amine dat nog aanwezig is in het reactiemengsel.

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Schema 1

Hoewel het gebruik van methyl isocyanoacetaat (4a, R3 = H) teleurstellende resultaten gaf, werden met methyl 2-fenylisocyanoacetaat (4b, R3 = Ph), dat gemakkelijk kan worden verkregen uit fenylglycine, redelijke tot zeer hoge opbrengsten gehaald. Zowel de amine- als de aldehydesubstituenten kunnen in hoge mate worden gevarieerd. Alifatische, aromatische, hetero-aromatische en olefinische substituenten geven goede resultaten. De diastereomere verhoudingen zijn tussen de 1,5:1 en 4:1 en de isomeren met R2 en R3 cis ten opzichte van elkaar zijn altijd in overmaat aanwezig. De MCR verloopt goed in methanol, dichloormethaan en tolueen, maar niet in THF. De grootte van de amine- en aldehydesubstituenten spelen een belangrijke rol. Slechts één sterisch grote zijgroep (R2 òf R3 = tBu or mesityl) is toegestaan voor een snelle reactie.

Om de mogelijkheden van onze MCR te vergroten werd de reactiviteit van andere α-zure

isocyanides ten opzichte van imines onderzocht (Hoofdstuk 3). Het makkelijk te synthetiseren 9-isocyanofluoreen 7 geeft toegang tot spiro-2-imidazolines 8 (Schema 2). Ook dit isocyanide is te combineren met een breed palet aan amines en aldehyden. Door gebruik te maken van bis-amines of bis-aldehyden kunnen zelfs bis-imidazolines gemaakt worden.

Schema 2

Hoewel 4-nitrobenzyl isocyanide 9 zowel onder standaard reactiecondities als bij hogere temperaturen niet reageert met imines, kan de vorming van 4-monogesubstitueerde 2-imidazolines 10 gekatalyseerd worden door 2 mol% AgOAc. De 4-(p-nitrofenyl)-imidazolines 10 worden aan de lucht geoxideerd tot imidazolen 11. Er zijn echter

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significante verschillen tussen de snelheden van oxidatie van de verschillende diastereomeren. Met behulp van DFT-berekeningen is een plausibele verklaring gegeven voor het snelheidsverschil tussen deze oxidaties die waarschijnlijk verlopen via een radicaalmechanisme.

Allyl iscocyanide werd ook onderzocht als mogelijk isocyanide in onze MCR.

Verschillende reactiecondities en katalysatoren werden getest, tot nu toe zonder succes. Om het verschil in reactiviteit tussen de verschillende isocyanides te rationaliseren werd weer gebruik gemaakt van DFT-berekeningen. Drie factoren blijken een rol te spelen: 1) de protonaffiniteit van het isocyanide (of het isocyanide-zilvercomplex); 2) de energie van de HOMO van het isocyanide anion; 3) de contributie van het (pz)-orbitaal van het carbanion in de HOMO.

Tenslotte werden in plaats van aldehyden ook ketonen getest als oxo-componenten in de

MCR. Hoewel dit in eerste instantie niet lukte, bleek AgOAc weer een geschikte katalysator.

Synthese van nieuwe NHC-complexen

Er zijn verschillende methoden bekend voor de synthese van complexen van N-heterocyclische carbenen (NHCs). Er zijn echter maar zeer weinig routes die leiden tot NHCs met niet-identieke substituenten op C–4 en C–5. Een voorbeeld is de één-potssynthese van thiourea gevolgd door een reductie met K of Na/K legering, gepubliceerd door Hahn. De procedure is zeer succesvol zolang er alifatische zijgroepen gebruikt worden, maar aromatische of nog gevoeligere substituenten zijn niet compatibel met de drastische reactiecondities. Aangezien de alkylering van 2-imidazolines gevolgd door deprotonering van de 2-imidazoliniumzouten een elegante en veelgebruikte route naar verzadigde NHCs is, hebben wij de bovenstaande MCR gebruikt voor de synthese van precursors voor nieuwe typen NHCs (Hoofdstuk 4).

Schema 3

De eerste experimenten werden uitgevoerd met het achirale spiro-2-imidazoline 12, zodat de vorming van diastereomeren (bijvoorbeeld in het geval van dimerisatie) voorkomen kon

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worden. De N–1 tert-butylgroep werd gekozen omdat grote stikstofsubstituenten over het algemeen dimerisatiereacties van NHCs voorkomen. Alkylering van 12 met methyljodide geeft imidazoliniumjodide 13 in bijna kwantitatieve opbrengst. Na deprotonering van 13 met natriumhydride kon geen stabiel, vrij carbeen worden geïsoleerd, daar de dimerisatie waarschijnlijk wordt gekatalyseerd door het imidazoliniumzout zelf. Deprotonering van 13 in de aanwezigheid van een coördinatief onverzadigd Rh(I)-complex geeft het stabiele Rh-NHC-complex 14, dat kan worden gezuiverd met behulp van kolomchromatografie, in hoge opbrengst (Schema 3). Toevoeging van een overmaat kaliumjodide zorgt voor volledige uitwisseling van het chloride op rhodium voor jodide. De structuur van 14 werd geverifieerd door middel van een kristalstructuurbepaling.

De algemene toepasbaarheid van de methode werd vervolgens aangetoond door variatie

van alle substituenten van de imidazoliniumzouten, het overgangsmetaal en de liganden. Een selectie van de 19 nieuwe NHC-complexen die zijn gesynthetiseerd is weergegeven in Figuur 1. De eigenschappen van de carbeenliganden zijn geanalyseerd met behulp van XRD, IR en NMR.

Figuur 1

Synthese van analoga van Nutlins door middel van functionalisering van de C–2 van 2H-2-imidazolines

De blokkering van de interactie tussen p53, een proteïne dat de groei van tumoren onderdrukt, en zijn natuurlijke remmer, MDM2, wordt gezien als een effectieve strategie in de strijd tegen kanker (Hoofdstuk 5). Een nieuwe klasse van 2,4,5-triaryl-2-imidazolines is recentelijk geïdentificeerd als actieve MDM2-blokkers. Wij hebben de MCR tussen amines, aldehyden en methyl 2-(p-chlorofenyl)-2-isocyanoacetaat gebruikt om imidazolines 19 met een Nutlin-skelet te synthetiseren (Schema 4).

De enige bekende routes voor de functionalisering van de C–2 van 2H-2-imidazolines

verlopen via deprotonering met organolithiumreagentia. Aangezien de delicate functionele groepen in onze moleculen daar niet tegen bestand zijn, hebben wij gezocht naar een milde methode voor de synthese van 2-aryl-2-imidazolines vanuit 2H-2-imidazolines. De reactie tussen in situ gegenereerde NHCs en zwavel werd beschouwd als een mogelijke route,

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aandezien thiourea en isothiourea gekoppeld kunnen worden met aryl- en vinylboorzuren (en stannanen) onder Liebeskind-Srogl-condities.

Schema 4

Helaas bleek het onmogelijk om de p-methoxybenzylgroep (PMB) af te splitsen van de N–1 van thiourea. Daarom werd een kleine omweg genomen. Oxidatie van imidazoliniumzouten met mCPBA geeft imidazolidin-2-onen 20 in goede opbrengsten. Ontscherming van N–1 of N–3, gevolgd door thionering met Lawesson’s reagens resulteert in de respectievelijke aryleringsprecursors 21a en 21b in zeer hoge opbrengsten. Liebeskind-Srogl-reacties in een single-mode magnetron (volgens Kappe) geeft de gewenste 2-aryl-2-imidazolines 22a en 22b in redelijke, nog niet geheel geoptimaliseerde opbrengsten.

Multicomponentsynthese van 3,4-dihydro-2-pyridonen

Om de mogelijkheden van isocyanides met zure α-protonen verder te verkennen werd de reactie tussen methyldiethylphosphonaat 23 , nitrillen 24, aldehyden 2 en isocyanoacetaten 4 bestudeerd (Hoofdstuk 6). In plaats van de verwachte 5-vinyl-2-imidazolines werden de tot nu toe onbekende 3-isocyano-3,4-dihydro-2-pyridonen 26 geïsoleerd (Schema 5).

Schema 5

Blijkbaar valt een gedeprotoneerd isocyanoacetaat met zijn α-koolstof via een 1,4-additie aan op het intermediaire 1-azadiëen 25, waarna er een lactamisering plaatsvindt. De nitril-, aldehyde- en isocyanoacetatesubstituenten kunnen gevarieerd worden in deze MCR, hoewel alifatische en sterk electronenarme aldehyden niet geschikt zijn. Tot nu toe geven 2-

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arylisocyanoacataten de beste opbrengsten en bovendien complete diastereoselectiviteit, maar ook isocyanoacetaten zonder extra electronenzuigende groep kunnen worden gebruikt. Het behoud van de veelzijdige isocyanogroep tijdens deze MCR, gecombineerd met de vrije amidestikstof, maakt de producten uitstekende kandidaten voor derivatisering tot bibliotheken van nieuwe Freidinger-type peptidomimetica via bijvoorbeeld Ugi-reacties.

Vooruitblik

In het laatste hoofdstuk (Hoofdstuk 7) zijn de verschillende projecten die beschreven staan in dit proefschrift geëvalueerd en zijn mogelijke toekomstige onderzoekslijnen uitgezet.

163

Dankwoord

Dat was het dan: een overzicht van bijna 5 jaar prutsen, lezen, nadenken, voorpellen, verbaasd zijn, teleurstellingen verwerken, experimenteren en improviseren, leren, vergaderen, meten en schrijven, tot stand gekomen met behulp van muziek, magnetronvoer, gevloek, zweet, slapeloze nachten, bizarre dromen, netwerken, overmatig kroegbezoek en een heleboel mensen met humor, toewijding, geduld en verstand van zaken. Tijd om een aantal namen te noemen dus... Romano, bedankt dat je mij de kans hebt gegeven om onderzoek te doen in jouw groep. Nog meer bedankt voor alles wat ik van je heb kunnen leren in die tijd inzake onderzoek doen, publicaties schrijven en relativeren. Je enthousiasme bij het samen bedenken van nieuwe plannen, de openheid waarmee we belangrijke en soms schijnbaar triviale zaken konden bespreken, de vrijheid die je me gaf in mijn onderzoek en het bepalen van mijn werktijden en je nauwkeurige correctiewerk hebben een grote bijdrage geleverd aan de totstandkoming van dit proefschrift. Ik hoop dat we zo af en toe nog eens onder het genot van het belangrijkste oplosmiddel voor de organisch chemicus terug kunnen kijken op deze mooie tijd, zolang je belooft nooit meer ‘Niemand laat zijn eigen kind alleen’ te zingen. Prof. Dr. Marinus Groen, uw enorme kennis van en ervaring met chemie heeft niet alleen bijzonder veel indruk op mij gemaakt, het heeft de groep ook verder geholpen. Bedankt voor alle kritische noten, al het precieze zoekwerk in de literatuur als ik weer eens een bizar idee had geopperd tijdens een werkbespreking en voor het feit dat ik altijd binnen kon lopen voor een praatje of goed advies. Prof. Dr. Koop Lammertsma, bedankt voor het vervullen van de taak van promotor in mijn eerste periode aan de VU, voor de adviezen (ook al leek ik ze uiteindelijk totaal te negeren, ze zetten me vaak wel aan het denken) en natuurlijk voor al uw vergeefse pogingen tot het beschermen van mijn trommelvliezen. I am grateful to the referees of this thesis, Prof. Dr. Cees Elsevier, Prof. Dr. David Aitken, Prof. Dr. Jieping Zhu, Dr. Jan van Maarseveen, Dr. Iwan de Esch and Dr. Floris van Delft for their time and interest in my work and for their input in different stages of the various projects. Prof. Dr. Alexander Dömling, thanks for your advice concerning the Nutlin project.

164

Zonder de kristalstructuurbepalingen door Dr. Martin Lutz en Prof. Dr. Anthony Spek was dit proefschrift een stuk dunner en een aantal publicaties zeker van mindere kwaliteit geweest. Martin, hartelijk dank voor het snelle lezen van mijn manuscripten en de hulp bij het maken van mooie plaatjes. Dr. Marcel Swart en Dr. Matthias Bickelhaupt, hartelijk dank voor de samenwerking op het gebied van de computerchemie. Jullie bereidheid om tijd te steken in de berekening van protonaffiniteiten heeft geleid tot een uitstekende aanvulling van ons JOC-paper. I would like to thank Prof. Dr. Ekkehardt Hahn for giving me the possibility to spend a few weeks in his lab in Münster. Dr. Mareike Jahnke, thanks for teaching me so much about synthesising carbenes in this short time. Tijdens mijn afstudeerstage in de groep van Prof. Dr. Henk Hiemstra en Dr. Jan van Maarseveen heb ik voor het eerst kennis gemaakt met onderzoek. In dit jaar ben ik er dan ook eindelijk achter gekomen wat ik nou eigenlijk wilde worden. Jan, zonder jouw steun tijdens en na mijn afstuderen was ik waarschijnlijk nooit aan een promotie begonnen. Johan, bedankt voor de extra skill points in laboratory practice. In de kleine maar zeer populaire werkgroep bio-organische chemie heb ik een groot aantal studenten mogen begeleiden. Ik ben blij dat jullie allemaal jullie best hebben gedaan om alle wilde plannen die ik smeedde, zo zorgvuldig mogelijk uit te voeren om te bewijzen dat ik weer eens ongelijk (en heel af en toe gelijk) had. Ook als het allemaal niet lukte, hebben jullie pogingen mij toch veel tijd bespaard en mij nog meer geleerd. Sibel, jij kwam al stage bij me lopen toen ik zelf nog maar net wist waar mijn zuurkast was. In de laatste week van jouw stage zijn we er achter gekomen dat het ontwikkelen van een katalytisch asymmetrische Ugi-4CC een stuk moeilijker is dan we van tevoren gedacht hadden. Emma en Anne, bedankt voor jullie inspanningen om startmaterialen te maken voor de totaalsynthese die we ooit in ons hoofd hadden. Helaas ben ik door de overdaad aan mogelijke projecten nooit aan het uitwerken van de ideeën toegekomen. Cong Jan, bedankt voor het maken van de verbindingen die ons Organic Letters-verhaal compleet maakten. Helaas bleken de Diels-Alder reacties in je vervolgonderzoek op papier makkelijker dan in de praktijk. Tanja, ook jouw project was zeer exploratief, en de resultaten waren meestal teleurstellend. Het moet toch wat troost gebracht hebben dat ook Dean de zo mooi bedachte cyclisaties niet aan de praat kreeg. Marien, bedankt voor het maken van verbindingen tijdens jouw eindproject, maar nog meer voor de muziek, de ontploffingen, de verhandelingen over scheve kapsels, puntschoenen en nutteloze riemen en het meenemen van vrienden zonder watervrees. Nanda, tijdens zowel je eindproject (katalyse met AgOAc) als je afstudeeropdracht (synthese van Nutlin-analoga) heb je voor belangrijke doorbraken gezorgd. Ook je literatuuronderzoek heeft flink bijgedragen aan het volume van dit proefschrift. En dit was allemaal zeker niet voor niets, want je naam staat straks boven twee

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mooie publicaties. Bovendien is mijn cd-collectie ook weer uitgebreid door jouw goede tips. Bart, jij wandelende grote bek op dunne pootjes, ik ben blij dat ik je nooit meer in je enge fietspakje hoef te aanschouwen. Wel bedankt voor je harde werk, je (redelijk) goede muzieksmaak en het altijd lachen om mijn flauwe grappen (iemand moet het doen). Anass, eigenlijk liep je stage bij Danielle, maar een deel van je werk is toch in mijn proefschrift terecht gekomen. Wat mooi dat de combinatie van de MCRs van Daan en mij weer een nieuwe MCR opleverde, de eerste die de isocyanidegroep intact houdt. Dulane, nadat Edith naar het noorden was vertrokken, heb je naast mij verder mogen stoeien met de lastige Rh-gekatalyseerde cyclisatiereacties in de magnetron. Het heeft veel tijd en moeite gekost, maar uiteindelijk heb je voor een aantal substraten toch goede condities weten te vinden. Hopelijk worden deze resultaten in de toekomst nog een keer gepubliceerd. Sander, door jouw literatuurscriptie begrijp ik een stuk meer van de eigenschappen van NHCs. Deze scriptie is ook een belangrijke leidraad geworden voor de lange introductie van Hoofdstuk 4. Behalve van studenten, heb ik hulp gehad van nog veel meer mensen bij het in elkaar zetten van dit boekje. Rob, ik snap dat je het soms jammer vindt dat je zelf niet zo heel veel tijd voor onderzoek hebt. Daar staat echter tegenover dat jij de groep op zo’n manier draaiende weet te houden dat de netto output veel hoger is. Ik mis je dagelijkse nieuwsanalyse. Manoe, bedankt voor het vele synthesewerk dat je voor me hebt gedaan toen ik het lab al uit was. Frans, bedankt voor al je hulpvaardigheid op de momenten dat ik weer een een koolstof kwijt was, de autosampler niet aan de praat kreeg of als ik echt geen idee had wat ik gekookt had. André, eeuwig dank voor al je hulp bij computerfalen (of in vele gevallen, mijn digibetie), je ADF berekeningen, de borrels en de lange gesprekken over ramen, sollicitaties en diepe sneeuw. Monica, thanks for synthesising the many dihydropyridones that filled Chapter 6 and our Organic Letters paper. Rachel, ik ben blij dat jij ook nog zoveel tijd hebt gestoken in het mooi afronden van het DHP project. Andreas, bedankt voor je hulp bij berekeningen en discussies over reactiemechanismen en het gevaar van wijn drinken. Marek, thanks for all the very quick HRMS measurements, even in the last days before I submitted my thesis. Judith, gelukkig kon ik altijd bij je terecht voor een praatje, talloze pennen en potloden, lekkere Italiaanse snacks of vragen over de eindeloze stroom formulieren die je nodig schijnt te hebben binnen een universiteit (ik snap nu pas dat Nederland wat dat betreft best meevalt vergeleken met de oosterburen). Miep, bedankt voor het zonder problemen overnemen van al deze taken. Hoewel veel dingen voor jou net zo onbekend waren als voor mij, heb je me toch geweldig door de laatste administratieve procedures gesleept. Danielle, kleine rooie, ik vond het prachtig om zo lang met je samen te mogen werken. Ongeveer tegelijk beginnen en eindigen smeedt toch wel een soort band. Ik ben ook blij dat je me net ingehaald hebt, waardoor ik nu lekker alles van jou kan afkijken. Mieke, je was er

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eigenlijk te kort bij (of wij te laat), maar gelukkig ben je nog vaak (met of zonder ladykiller Rody) op komen draven bij Beaujolaisfeesten, huisfeestjes of slempavonden in Mokum. Bas, ik geloof ook dat we een winnaar hebben wat betreft aanwezigheid op feestjes en borrels. Ik kan me er geen herinneren waar jij ontbrak. Slechts lof daarvoor! Alle andere oud-collega’s en studenten die ooit in de groep hebben rondgelopen: Bedankt voor de supersfeer al die jaren, met name Fedor (voor de allermooiste uitspraken), Chris (voor experimenteer- en schrijftips), Niels (sorry voor de herrie, poldermans), Professor Bickelhaupt, Marius (voor discussies over correct Nederlands), wijlen Martien de Bolster (voor de juiste nomenclatuur), Bas (voor het beste vacuüm), Sander (we willen paintballen!), Maurice (voor de muziek en de zangeresjes), Lisette, Peter, Helen, Dean (yeah, but no, but yeah, but no, but...), Alessia (smurfinnetje, the reunion was short but a lot of fun), Edith, Wannes, Rosa (mijn verslaving aan David Lynch-films heb ik aan jou te danken), Erik (voor de mooie plaatjes in alle presentaties), Halil (wanneer gaan we nou modderworstelen?), Mark (de grootste sensatie sinds Jamai), Arjan, Tijmen (voor de beste Tour-tips), Jos, Willem-Jan (voor het tijdelijke onderdak), Martin (doe mij maar gewoon een bord warm eten), Loes, Bart N. en Guido. Ook de MedChem-groep wil ik niet vergeten. Vele borrels heb ik namelijk gedronken met Mark, Michael, Janneke (toen ze nog jong was), Oscar, Niels en Sjef. Mark, vanaf de eerste dag dat je als stagiair bij de VU kwam stond de tap open (de legendarische Stelling-borrel) en die is nooit meer dicht gegaan. Gouden feesten hebben we gevierd bij de biologen, bij de geologen, in Paradiso en in een hele serie foute Amsterdamse kroegen. Ik ben blij dat je straks naast me staat als paranimf. Jasper, sinds jouw “of we hakken allemaal onze rechterarm af” heeft onze vriendschap me waarschijnlijk door de studie heen geholpen. De briljante momenten, van Amsterdam tot Gran Canaria en van Utrecht tot Praag, zijn ontelbaar. Dat er nog vele mogen komen! Ik ben ook vereerd dat je je in een net pak wilt hijsen voor mijn promotie. Dank ook aan de oud-Villa-crew: Chris, Jordy, Donald, Roger en Ferry; Robin en Mariska; Ronald en Annemiek; Fleur; Jan; Michel; Willem; Jeroen L.; Jitte en Susan; Ron; de voormalige UVA-collega’s; mijn nieuwe MPI-collega’s; de Praha Pivogang; de Leuven-boys en alle anderen, zonder wie dit leven zoveel saaier zou zijn. Als laatste: Oscar, Petra, Valentijn, Gabrielle, Pa en Ma, ik laat het misschien niet altijd blijken, maar ik ben blij en trots dat jullie mijn familie zijn. Bedankt voor de fantastische basis waar ik altijd op terug kan vallen.

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“…We are here to laugh at the odds and live our

lives so well that Death will tremble to take us.”

Charles Bukowski

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